Top Line: For locally-advanced esophageal squamous cell carcinoma (SCC), is understanding upfront surgical pathology versus pathologic response to neoadjuvant chemoradiation a better guidepost for outcomes?
The Study: A single-center Chinese phase 3 trial randomized 230 evaluable patients with resectable locally-advanced thoracic ESCC (cT2–4a or N+) to standard neoadjuvant chemoradiation (NCRT, n=118) versus upfront surgery with planned adjuvant chemoradiation (n=112). Following surgery, only 65 received adjuvant chemoradiation as intended, 23 chemotherapy alone, 15 radiotherapy alone, and 9 declined any adjuvant therapy. Chemoradiation was delivered via IMRT 2 Gy x 20 = 40 Gy with concurrent paclitaxel/carboplatin. Overall survival at 5 years was essentially identical—59% with NCRT versus 60% with upfront surgery. Toxicity and perioperative complication rates were comparable, though NCRT demonstrated clear pathologic responses: 72% of patients receiving upfront surgery had pathologic nodal involvement versus only 29% followed NCRT, rates of tumor thrombus were 43% versus 9% and of neural invasion were 39% versus 19%. Ultimately, 29% of patients achieved a complete pathologic response to NCRT, of whom an impressive 77% were still alive at 5 years. The similar survival outcomes despite impressive pathologic downstaging is understandable: “Patients with poor pathological response continue to have unfavorable outcomes, and when they constitute the majority they can dilute any population-level advantage of NCRT.” Strategies to increase the proportion of patients who achieve a complete pathologic response are underway, including incorporating immunotherapy.
TBL: “The clinical challenge going forward is to prospectively identify patients likely to attain pCR: those expected to respond well could preferentially receive neoadjuvant therapy (and thereby avoid overtreatment after surgery); for those unlikely to respond, surgery followed by AT remains a valid option.” | He, JAMA Netw Open 2026
The Study: A single-center Chinese phase 3 trial randomized 230 evaluable patients with resectable locally-advanced thoracic ESCC (cT2–4a or N+) to standard neoadjuvant chemoradiation (NCRT, n=118) versus upfront surgery with planned adjuvant chemoradiation (n=112). Following surgery, only 65 received adjuvant chemoradiation as intended, 23 chemotherapy alone, 15 radiotherapy alone, and 9 declined any adjuvant therapy. Chemoradiation was delivered via IMRT 2 Gy x 20 = 40 Gy with concurrent paclitaxel/carboplatin. Overall survival at 5 years was essentially identical—59% with NCRT versus 60% with upfront surgery. Toxicity and perioperative complication rates were comparable, though NCRT demonstrated clear pathologic responses: 72% of patients receiving upfront surgery had pathologic nodal involvement versus only 29% followed NCRT, rates of tumor thrombus were 43% versus 9% and of neural invasion were 39% versus 19%. Ultimately, 29% of patients achieved a complete pathologic response to NCRT, of whom an impressive 77% were still alive at 5 years. The similar survival outcomes despite impressive pathologic downstaging is understandable: “Patients with poor pathological response continue to have unfavorable outcomes, and when they constitute the majority they can dilute any population-level advantage of NCRT.” Strategies to increase the proportion of patients who achieve a complete pathologic response are underway, including incorporating immunotherapy.
TBL: “The clinical challenge going forward is to prospectively identify patients likely to attain pCR: those expected to respond well could preferentially receive neoadjuvant therapy (and thereby avoid overtreatment after surgery); for those unlikely to respond, surgery followed by AT remains a valid option.” | He, JAMA Netw Open 2026