Pathological Complete Response Is Not Always the Best Outcome: Survival Advantage of Minimal Residual Disease After Esophagectomy

Abstract Background Esophageal cancer (EC) remains one of the most aggressive malignancies worldwide and is associated with high morbidity and mortality. In patients with locally advanced, resectable EC, standard treatment consists of either neoadjuvant chemoradiotherapy according to the CROSS protocol or perioperative chemotherapy following the FLOT protocol, both followed by esophagectomy. Since publication of the CheckMate 577 trial, patients with residual tumor after neoadjuvant chemoradiotherapy routinely receive adjuvant immunotherapy with nivolumab. Aims To evaluate survival and recurrence outcomes according to pathological tumor stage after esophagectomy. Methods We retrospectively analyzed all patients who underwent curative-intent esophagectomy for esophageal cancer (adenocarcinoma or squamous cell carcinoma) at our hospital between 2014 and 2024. Results A total of 235 patients were included, of whom 204 (86.4%) had adenocarcinoma.. Neoadjuvant treatment consisted of the CROSS protocol in 187 (78.9%) patients, the FLOT protocol in 25 (10.5%) patients, and other regimens in 5 (2.1%) patients. 20 (8.4%) patients had no preoperative therapy. Histopathological analysis revealed pathological tumor stages T0 (pathological complete response) in 50 (21.3%) patients, T1 in 50 (21.3%), T2 in 42 (17.7%), T3 in 88 (37.4%), and T4 in 5 (2.1%) patients. Overall survival was poorest in patients with T4 tumors, followed by T3 and T2 stages. Notably, patients with minimal residual disease (T1) demonstrated the most favorable survival outcomes, exceeding those observed in patients with pathological complete response (Figure 1). Conclusion Patients with minimal residual disease (T1) exhibited superior survival and lower recurrence rates compared to patients with pathological complete response. This may be explained by routine use of adjuvant nivolumab in patients with residual disease, while patients with complete response currently don’t receive immunotherapy. These findings, supported by previously reported data from our cohort showing recurrence rates exceeding 30% even after complete response, suggest that the role of adjuvant immunotherapy in this subgroup warrants further investigation.Figure 1:Overall survival according to postoperative histopathological T stage.For image description, please refer to the figure legend and surrounding text.