Postoperative Distant Recurrence Pattern for Resectable Esophageal Cancer Treated With Neoadjuvant Therapy: A Systematic Review and Meta-Analysis

Background While neoadjuvant therapy combined with esophagectomy have revolutionized survival outcomes in resectable esophageal cancer, the challenge of postoperative distant metastatic recurrence remains a critical issue. Currently, the incidence and patterns of distant metastasis after these neoadjuvant treatments are still poorly understood. We performed a meta-analysis to evaluate the incidence and pattern of distant failure in patients treated with neoadjuvant therapy followed by surgery. Methods A systematic literature search was conducted on Pubmed, Embase, and web of science between 2012 and 2024 to identify phase II/III randomised controlled trials and prospective cohort studies reporting postoperative metastatic recurrence after neoadjuvant chemoradiotherapy [nCRT] and neoadjuvant chemotherapy [nCT]; neoadjuvant immunotherapy was not included due to limited data on recurrence outcomes. Patient characteristics and distant recurrence related information were extracted. Results From a total of 6768 studies screened, 19 studies eligible (n = 1801, 13 nCRT and 6 nCT) met the inclusion criteria. The pooled incidence of distant recurrence was higher in the nCRT group compared to the nCT group (0.30 [95%CI: 0.24–0.36] vs 0.24 [95%CI: 0.17–0.35], respectively, Fig. 1A-B). The most common sites of distant recurrence were lung, liver and bone. On multivariable meta-regression adjusted for gender, age, follow-up time, histology and neoadjuvant treatment completion rate, age was associated with a higher incidence of distant recurrence (adjusted incidence rate ratio(IRR): 1.06, 95% CI 1.01–1.12, Fig. 1C). Conclusion This study provides a comprehensive evaluation of postoperative distant recurrence in patients with resectable esophageal cancer treated with the current standard of neoadjuvant therapy. While nCRT achieves higher pathological complete response rates, it is associated with a relatively higher incidence of distant recurrence compared to nCT. These findings highlight the need for further research to optimize preoperative treatment strategies, aiming to improve long-term outcomes and reduce the burden of distant metastasis in this challenging patient population.