Esophageal Cancer: Adjuvant and Neo-Adjuvant Therapies
The survival benefit of neoadjuvant therapy for esophageal squamous cell carcinoma (ESCC) remains controversial, as landmark trials were conducted predominantly in adenocarcinoma populations. This study evaluated the association between neoadjuvant therapy and long-term survival in a large international multicenter ESCC cohort using propensity score methods and multivariable Cox regression.
We retrospectively analyzed 2,449 patients with ESCC who underwent curative esophagectomy at five institutions across three countries (Japan, China, and South Korea) between 2008 and 2022. Patients receiving neoadjuvant therapy (n=941) were compared with a surgery-first cohort (n=880) after excluding 41 cases with inconsistent survival data. Propensity score matching (PSM) 1:1 was performed using nearest-neighbor matching (caliper=0.1 SD of logit propensity score) with exact matching on center, adjusting for sex, age, clinical T and N stage. Inverse probability of treatment weighting (IPTW) with trimming (1st–99th percentile) served as a sensitivity analysis. Center-stratified univariate and multivariable Cox proportional hazards regression were applied. Primary endpoints were overall survival (OS) and disease-free survival (DFS).
In analysis, neoadjuvant therapy appeared protective for OS (HR 0.60, 95% CI 0.48–0.75, p<0.001) while DFS was worse (HR 1.57, 95% CI 1.34–1.84, p<0.001). This discordant finding reversed after center-stratified Cox regression, revealing substantial confounding by center. Univariate analysis showed neoadjuvant therapy was associated with worse OS (HR 2.22, 95% CI 1.75–2.83, p<0.001) and DFS (HR 2.31, 95% CI 1.89–2.82, p<0.001). Multivariable analysis confirmed neoadjuvant therapy as an independent predictor of worse OS (HR 1.48, 95% CI 1.11–1.96, p=0.007) and DFS (HR 1.39, 95% CI 1.09–1.77, p=0.007). PSM yielded 255 pairs; after matching, neoadjuvant therapy was associated with worse OS (HR 1.56, 95% CI 1.05–2.30, p=0.027) and DFS (HR 1.60, 95% CI 1.18–2.19, p=0.003). IPTW sensitivity analysis yielded consistent results (OS: HR 2.21, 95% CI 1.74–2.82; DFS: HR 2.30, 95% CI 1.89–2.81; both p<0.001).
In this international multicenter analysis of 2,449 ESCC patients, neoadjuvant therapy was not associated with improved survival after esophagectomy and remained an independent predictor of worse OS and DFS across univariate, multivariable, PSM, and IPTW analyses. These findings underscore the critical importance of histology-specific evidence and support the urgent need for contemporary randomized controlled trials designed specifically for ESCC populations.
Si-miao Lu, Yi Zhu, Qiulin Shi et al.· Diseases of the esophagus· 0 citations
Esophageal Cancer: Surgical Treatment of Esophageal Cancer – early outcomes and complications
Persistent moderate-to-severe symptoms after minimally invasive esophagectomy (MIE) remain poorly characterized. While patient-reported outcomes (PROs) are increasingly recognized as important endpoints in surgical oncology, the prevalence, risk factors, optimal intervention timing, and prognostic impact of persistent postoperative symptom burden in esophageal squamous cell carcinoma (ESCC) patients have not been systematically evaluated. Understanding these factors is essential for developing evidence-based, timely symptom management strategies to improve postoperative recovery and quality of life.
We retrospectively analyzed 345 ESCC patients who underwent MIE at a single tertiary center. Symptoms were assessed using the MDASI, EORTC QLQ-C30, and QLQ-OES18 at baseline through 6 months postoperatively. Persistent moderate-to-severe symptoms at postoperative month 3 were defined by composite criteria (meeting any one): MDASI ≥3 core symptoms scoring ≥4; QLQ-C30 ≥2 functional domains below 66.7; or OES18 ≥2 symptom domains above 33.3. Independent risk factors were identified by multivariable logistic regression. Symptom trajectory analysis identified the critical divergence timepoint. Kaplan–Meier analysis, log-rank tests, multivariable Cox regression, and propensity score matching (1:1, 81 pairs) evaluated associations between symptom persistence and overall survival (OS) and disease-free survival (DFS).
At postoperative month 3, 89 patients (25.8%) met criteria for persistent moderate-to-severe symptoms. Independent risk factors were anastomotic leak (OR=7.92, P<0.001), adjuvant therapy (OR=3.05, P<0.001), and smoking history (OR=2.58, P=0.029); male sex was protective (OR=0.34, P=0.013). Predictive model AUC was 0.734. Symptom trajectories diverged at postoperative day 14. Five-year OS (63.5% vs 66.1%, HR=1.16, P=0.478) and DFS (72.9% vs 73.8%, HR=0.87, P=0.554) showed no significant differences. After propensity score matching (81 pairs), OS remained non-significant (HR=0.94, P=0.796), while DFS favored the persistent group (HR=0.55, P=0.029), potentially mediated by higher adjuvant therapy exposure.
Approximately one-quarter of post-MIE ESCC patients experience persistent moderate-to-severe symptoms at 3 months, primarily driven by anastomotic leak and adjuvant therapy. Symptom persistence does not adversely affect overall survival; its association with improved DFS likely reflects the tumor-control benefit of adjuvant therapy. Postoperative day 14 represents the critical symptom trajectory divergence point, providing an optimal window for initiating targeted PRO-based intervention.
Si-miao Lu, Yi Zhu, Yong-tao Han et al.· Diseases of the esophagus· 0 citations
Esophageal Cancer: Surgical Treatment of Esophageal Cancer – early outcomes and complications
Postoperative complications following oesophagectomy occur in 25–60% of patients, yet traditional patient-reported outcome (PRO) assessment relies on standardised questionnaires with limited reliability, particularly among elderly patients with low health literacy. We aimed to develop and externally validate a multimodal artificial intelligence (AI) system that automates PRO assessment from natural patient conversations and provides early warning of major postoperative complications.
We conducted a prospective observational study at a tertiary cancer center, enrolling consecutive patients undergoing esophagectomy.The development cohort (Centre 1, n=196) and the temporally independent external validation cohort (Centre 2, n=103) were recruited sequentially. Using the validated Patient Symptom Assessment for Oesophageal Cancer (PSA-ESO) instrument, we collected trimodal recordings (video, audio, text) at up to 25 timepoints per patient, yielding 6,813 evaluable assessments. We fine-tuned the Qwen2.5-Omni-7B multimodal large language model with LoRA adaptation for two tasks: automated PRO symptom grading (Task A) and Temporal Transformer-based early warning of Clavien-Dindo grade II or higher complications (Task B). In a prospective implementation substudy (n=62), we evaluated the clinical impact of real-time alerts on time-to-intervention.
In the external validation cohort, the trimodal PRO assessment achieved a weighted kappa of 0.801 (95% CI 0.73–0.87) and ICC of 0.858 against expert consensus, significantly outperforming audio-text bimodal (kappa 0.754, p<0.0001) and text-only (kappa 0.689, p<0.0001) configurations. The early warning model achieved an AUROC of 0.873 (95% CI 0.82–0.93) with a mean detection lead time of 28.7 hours before clinical diagnosis. The system detected 76.1% of symptom under-reporting cases. In the implementation substudy, real-time alerts reduced median time-to-intervention from 14.2 hours to 6.8 hours (p=0.003) and were associated with shorter ICU stays (3.1 vs 5.4 days, p=0.028).
An end-to-end multimodal AI system can accurately automate PRO assessment from natural patient conversations and provide clinically meaningful early warning for postoperative complications, with external validation confirming generalisability across cohorts. This conversation-based approach represents a paradigm shift from questionnaire-based PRO evaluation in surgical oncology, with particular relevance for populations with limited health literacy.
Si-miao Lu, Yi Zhu, Yong-tao Han et al.· Diseases of the esophagus· 0 citations
Surgical timing, particularly esophagectomy performed in February, is associated with inferior long-term survival in ESCC patients, and concurrent low burnout levels during this period suggest that reduced surgical volume and altered case selection during the holiday season, rather than staff fatigue, may underlie this disparity.
Si-miao Lu, Yi Zhu, Yong-tao Han et al.· Diseases of the esophagus· 0 citations
Esophageal Cancer: Surgical Treatment of Esophageal Cancer
Preoperative risk stratification for esophagectomy complications relies on clinical prediction models; however, their discriminative performance in multi-institutional settings remains poorly defined. We hypothesized that standard preoperative variables would demonstrate limited predictive validity across heterogeneous surgical cohorts.
We analyzed 2,490 patients undergoing esophagectomy across four institutions in Asia (total n=2,490; individual center n range 75–1,012). Four outcomes were studied: recurrent laryngeal nerve palsy (RLNP), anastomotic leak (AL), pulmonary complications (PC), and vocal cord palsy (VCP). Logistic regression models with bootstrap-validated odds ratios (1,000 iterations) were evaluated by 5-fold cross-validated AUC. SHAP (SHapley Additive exPlanations) via Gradient Boosting Machines quantified variable importance. Decision curve analysis (DCA) assessed net clinical benefit across threshold probabilities 2–70%. Association between tumor location and each complication was assessed using chi-squared tests.
All prediction models demonstrated poor-to-fair discrimination: RLNP AUC 0.533, AL AUC 0.586, PC AUC 0.676, and VCP AUC 0.556. Tumor location was the only statistically significant categorical predictor of RLNP—upper/cervical location was associated with higher RLNP incidence compared to middle thoracic tumors (39.1% vs. 28.0%; OR 1.22, 95%CI 1.05–1.42; p=0.009). No significant association was observed between tumor location and AL, PC, or VCP. DCA demonstrated negligible clinical net benefit for RLNP and AL models; only the PC model provided modest benefit (max net benefit gain +0.057) at threshold probabilities of 5–20%. SHAP analysis identified FEV1%, PNI score, and BMI as the highest-importance variables for RLNP prediction, with tumor location ranking sixth—indicating that location contributes a statistically real but clinically modest signal.
Standard preoperative variables are insufficient for individualized risk stratification of RLNP, anastomotic leak, or vocal cord palsy after esophagectomy. Statistical significance (p=0.009 for location–RLNP association) does not translate to clinically meaningful predictive power (AUC 0.533). Tumor location should be incorporated into RLNP preoperative counseling. Improved prediction will require prospective integration of real-time intraoperative data. Pulmonary complication risk approaches clinically actionable prediction (AUC 0.676) and may guide respiratory prehabilitation targeting.
Si-miao Lu, Yi Zhu, Yong-tao Han et al.· Diseases of the esophagus· 0 citations
A multimodal early warning system integrating PROs, laboratory trajectories, and large language model-extracted clinical text features to enable real-time, automated complication surveillance substantially outperforms single-modality approaches for detecting postoperative complications after esophagectomy.
Si-miao Lu, Yi Zhu, Yong-tao Han et al.· Diseases of the esophagus· 0 citations
Postoperative CRP trajectory patterns are significantly associated with complication severity after esophagectomy, and the High-Persistent trajectory identifies a high-risk subgroup, and the D3/D1 ratio enables early risk stratification by POD 3.
Si-miao Lu, Yi Zhu, Yong-tao Han et al.· Diseases of the esophagus· 0 citations
The natural product compounds CNP0456830 and CNP0467494 exhibited the lowest binding free energies for both EGFR and PIK3CA, identifying them as the most promising dual-target inhibitors.
Si-miao Lu, Yi Zhu, Yong-tao Han et al.· Diseases of the esophagus· 0 citations
