Letter to the Editor: Comment on “ Is Site of Radiation Therapy Associated With Pathologic Complete Response in Patients With Locally Advanced Esophageal Cancer?”

Dear Editor,

We were intrigued by the study by Singh and colleagues, which examined whether the site of neoadjuvant chemoradiation (CRT), community center (CC) vs high-volume center (HVC), influences pathologic complete response (pCR) and node-negative (ypN0) rates in 708 patients with locally advanced esophageal cancer (EC) undergoing surgery at an HVC. ¹ The authors observed no significant differences in pCR or ypN0 rates after adjusting for demographic and clinical factors. These findings contribute meaningfully to understanding treatment efficacy across healthcare settings. Nevertheless, 2 key concerns warrant attention for a more balanced interpretation of the results.

First, the unbalanced distribution of several variables between the HVC and CC groups raises questions about whether the outcomes were truly comparable. For instance, clinically node-positive (cN⁺) disease, a well-recognized adverse prognostic factor, was more frequent in the HVC group (72% vs 61%; P = .002), and although this difference attenuated to a statistical trend (P = .10) after adjustment, the directional imbalance suggests that HVCs treated patients with more advanced nodal disease. Likewise, the mean radiation dose was higher at HVCs (5195 vs 4944 cGy; P < .001). Thus, while the HVC cohort was disadvantaged by greater disease burden, this effect may have been offset by higher radiation doses, consistent with prior studies linking dose escalation to enhanced tumor response.^2,3 Taken together, the observed absence of significant differences in pCR or ypN0 rates may therefore represent a balance between adverse baseline risk and treatment intensification rather than true equivalence, implying that HVCs may confer a relative therapeutic advantage for patients with poor prognostic features. ⁴

Second, although pCR and ypN0 are valuable surrogate endpoints, overall survival remains the most clinically meaningful measure of benefit in any cancer population, including patients with EC. Population-based analyses consistently demonstrate that treatment at HVCs is associated with superior overall survival and reduced perioperative mortality, even when tumor-level responses such as pCR appear comparable.^4,5 This survival advantage is likely multifactorial. HVCs typically offer more robust perioperative infrastructure, encompassing experienced surgical teams, advanced critical care units, and coordinated multidisciplinary management that collectively reduce postoperative morbidity and mortality. Beyond surgical expertise, these centers often implement structured care pathways, comprehensive nutritional and rehabilitative support, and seamless integration of oncology subspecialists. Such systemic strengths enhance treatment adherence, mitigate toxicity, and improve recovery, thereby fostering greater long-term survival irrespective of immediate pathological outcomes. Accordingly, although Singh and colleagues did not observe significant differences in pCR or ypN0 rates, ¹ the broader evidence base underscores that centralization of EC management to HVCs remains critical for optimizing survival outcomes.^4,5

In conclusion, Singh and colleagues provide valuable evidence that immediate pathological outcomes after neoadjuvant CRT may be comparable across institutions. ¹ However, imbalances in disease burden and radiation dose warrant caution in assuming equivalence. The broader literature continues to support centralization of esophageal cancer care to high-volume centers as key to optimizing safety, toxicity, and survival outcomes.^4,5 We thank the authors for advancing this important discussion on where—and how—complex multimodality EC care is best delivered.