Is postoperative adjuvant therapy necessary for esophageal cancer patients with pathological complete response after neoadjuvant treatment?

BACKGROUND: Current National Comprehensive Cancer Network (NCCN) guidelines recommend omission of adjuvant therapy in esophageal cancer patients achieving pathological complete response (pCR) following neoadjuvant treatment. However, 20-40% of these patients experience disease recurrence, potentially indicative of residual micrometastatic disease. This retrospective study evaluates survival outcomes between adjuvant therapy and observation in pCR populations. METHODS: We analyzed 184 esophageal cancer patients with confirmed pCR after completed neoadjuvant therapy at Hebei Medical University Fourth Hospital (2012-2024). All patients completed at least two cycles of neoadjuvant chemotherapy or chemoimmunotherapy, or full-dose neoadjuvant chemoradiotherapy (40-50.4 Gy). Patients were stratified into adjuvant therapy (n = 66) and observation (n = 118) cohorts. The comparison between the two groups was performed using inverse probability of treatment weighting (IPTW) to adjust for confounding factors. Kaplan-Meier methodology with log-rank testing and Cox proportional hazards models evaluated disease-free survival (DFS) and overall survival (OS). Based on the identified high-risk prognostic factors from survival analyses, we proposed a risk-adapted clinical decision-making algorithm for postoperative adjuvant therapy selection among pCR patients. RESULTS: Multivariate analysis identified clinical T4a stage as an independent prognostic risk factor (P = 0.001). With median follow-up of 37.1 months, adjuvant therapy demonstrated superior 3-year DFS (P = 0.0027) and marginal OS improvement (P = 0.057). Significant OS benefits emerged in cT4a-stage (P = 0.034) and clinical lymph node-positive subgroups (P = 0.048). Adjuvant therapy recipients experienced prolonged median recurrence-free interval (35.50 vs 12.79 months, P < 0.001) and reduced recurrence incidence (1.51% vs 15.25%, P < 0.001). In the adenocarcinoma subgroup (n = 26), all recurrent events were distant metastases (7.69%) without local locoregional failure. Proposed risk-adapted algorithm for pCR esophageal cancer after neoadjuvant therapy: adjuvant therapy recommended for high-risk (cT4a any cN) and moderate-risk (cN + cT2-3) subgroups; shared decision-making for standard-risk (cT2-3N0) balancing benefit and toxicity. CONCLUSION: Clinical T4a stage predicts adverse outcomes in pCR patients. Adjuvant therapy reduces and delays recurrence in pCR esophageal cancer patients, improving survival, especially in high-risk subgroups (cT4a, cN+). These findings challenge current guideline recommendations and support risk-adapted adjuvant strategies in esophageal cancer.