Neoadjuvant immunochemotherapy with or without radiotherapy for locally advanced esophageal squamous cell carcinoma: a pooled analysis of two prospective single-arm clinical trials

The integration of immune checkpoint inhibitors (ICIs) into the treatment of locally advanced esophageal squamous cell carcinoma (LA-ESCC) represents a current research focus. This study aims to evaluate the value of radiotherapy in the context of ICIs combined with neoadjuvant chemotherapy (nICT) by pooling data from two prospective trials: one employing sintilimab plus chemotherapy (the nICT group, ChiCTR1900026593), and another utilizing toripalimab combined with chemotherapy and short-course radiotherapy [the neoadjuvant immunotherapy combined with chemoradiotherapy (nICRT) group, ChiCTR2100045104].

Methods

Both single-center, single-arm trials employed identical eligibility criteria. Trial procedures are detailed in Supplemental Digital Content Materials, available at: http://links.lww.com/JS9/H82. To ensure assessment quality, two senior radiologists independently reviewed baseline imaging for clinical T-staging, while two senior pathologists performed blinded independent re-evaluation and classification of surgical specimens^[1^]. The study received ethics approval and complies with the TITAN guidelines 2025^[2^]. Comprehensive methodological details available in Supplemental Digital Content Materials, available at: http://links.lww.com/JS9/H82.

Results

The nICT group comprised 45 patients (median follow-up 48 months) and the nICRT group 20 patients (median follow-up 40 months). As of 13 November 2024, the overall cohort median follow-up was 45 months (IQR 22–50 months). The nICRT group presented with more advanced disease, including higher proportion of stage IVA (39% vs 11%, P = 0.012; Supplemental Digital Content Table S1, available at: http://links.lww.com/JS9/H82), cT3–4a tumors (95% vs 45%, P<0.001), and greater pretreatment lymph node involvement (45% vs 33%). Pathological complete response (pCR) rate was significantly higher in the nICRT group (55% vs 18%, P = 0.002).

While survival outcomes did not significantly differ between groups (Fig. 1, P > 0.05), the nICRT group exhibited a trend of better local recurrence-free survival (LRFS; Fig. 1C, P = 0.066). Post hoc analysis indicated low statistical power (22.8%) to detect differences in 3-year PFS.

Figure 1.

Kaplan–Meier analysis of (A) progression-free survival (PFS), (B) overall survival (OS), (C) local recurrence-free survival (LRFS), (D) metastasis-free survival (MFS) between the two groups. CI, confidence interval; HR, hazard ratio; nICT, neoadjuvant immunotherapy combined with chemotherapy; nICRT, neoadjuvant immunotherapy combined with chemoradiotherapy.

Within the nICT group, patients achieving pCR demonstrated significantly superior overall survival (OS) compared to non-pCR patients (Fig. 2B, P = 0.033), primarily attributed to improvements in metastasis-free survival (MFS) (Fig. 2D, P = 0.066). In the nICRT group, pCR patients exhibited significantly superior progression-free survival (PFS) (Fig. 2E, P = 0.029), with driven by enhanced LRFS (Fig. 2G, P = 0.004). After 45 months, both recurrence rate (53% vs 40%) and the locoregional recurrence rate (LRR) (49% vs 25%, P = 0.071) were higher in the nICT group (Supplemental Digital Content Table S5, available at: http://links.lww.com/JS9/H82).

Figure 2.

Kaplan–Meier analysis of (A) progression-free survival (PFS), (B) overall survival (OS), (C) local recurrence-free survival (LRFS), (D) metastasis-free survival (MFS) according to whether achieving pCR in the nICT group; (E) PFS, (F) OS, (G) LRFS, (H) MFS according to whether achieving pCR in the nICRT group. CI, confidence interval; HR, hazard ratio; pCR, pathological complete response; nICT, neoadjuvant immunotherapy combined with chemotherapy; nICRT, neoadjuvant immunotherapy combined with chemoradiotherapy.

Discussion

Despite more advanced baseline disease, the nICRT regimen achieved a higher pCR rate without compromising survival outcomes. The nICT approach avoids radiotherapy-related toxicity while maintaining efficacy comparable to triplet chemotherapy^[3^]. Although the nICRT protocol utilized reduced radiotherapy fields and lower biological dose, its efficacy was not inferior to traditional neoadjuvant chemoradiotherapy (nCRT) when combined with extended two-field lymphadenectomy^[4,5^]. Further analysis indicates that under the current extended two-field lymphadenectomy, completely replacing radiotherapy in nICT may reduce the risk of MFS, but LRR rate remains elevated. Moreover, the differential prognostic implications of pCR are noteworthy: in the nICT group, pCR primarily predicted OS benefit, whereas in the nICRT group, pCR was associated with reduced local recurrence risk. Notably, while the addition of ICIs decreased distant metastasis (DMS) probability, most patients in the nICRT group who did not achieve pCR experienced recurrence, suggesting poor response to nICRT may strongly correlate with tumor recurrence risk.

This study provides the first long-term comparison between nICT and nICRT, with data quality ensured through centralized blinded review. This study has limitations including baseline imbalances, retrospective design, modest sample size, and exploratory nature of nICRT regimen. Future studies should incorporate biomarker analyses to identify patients most likely to benefit from radiotherapy addition to nICT.

Conclusions

Despite more advanced disease in the nICRT group, OS remained comparable to the nICT group, with a trend toward improved LRFS. This suggests radiotherapy may help reduce local recurrence risk in selected patients, though larger studies are needed for validation.

Ethical approval

This study was conducted according to the Declaration of Helsinki and received ethical approval from the Institutional Review Board and Ethics Committee of Jiangsu Cancer Hospital (approval number: AF-SOP026-01). The requirement for informed consent was waived due to the anonymity of the data.

Consent

The requirement for informed consent was waived due to the anonymity of the data.

Sources of funding

This work was funded by the Talents Program of Jiangsu Cancer Hospital, Wu Jieping Medical Foundation (320.6750.2020-13-5), a Research Project of Jiangsu Cancer Hospital (No. ZL202202), a Jiangsu Province “333” Talents Project (No. LGY2018070), the China Postdoctoral Science Foundation (No. 2017M621679), the National Natural Science Foundation of China (No. 81602381), the Jiangsu Province Capability improvement Project through Science, Technology and Education, Jiangsu Provincial Medical Innovation Center (No. CXZX202224), and the Yishan Research Project of Jiangsu Cancer Hospital (YSZD202403).

Author contributions

Y.L., M.J., Z.Z., J.Y., N.J., and X.Z. contributed to study conception. Y.L., M.J., Y.W., L.G., X.H., Z.G., J.Z., and B.Y. contributed to the development of methodology. Z.Z., Y.X., F.J., D.F., G.C., X.S., L.Z., and C.K. collected all data. Y.L., Z.Z., G.X., and Y.Z. analyzed the data. Y.L. and M.J. wrote the original draft of the manuscript. All authors contributed to its review and editing. J.Y., N.J., and X.Z. supervised the study and acquired funding. All authors had full access to all data and reviewed, verified, and consented to the published version of the manuscript. All accept the responsibility to submit the manuscript for publication.

Conflicts of interest disclosure

All the authors declare to have no conflicts of interest relevant to this study.

Research registration unique identifying number (UIN)

Both trials were registered with ClinicalTrials. gov (the nICT group: ChiCTR1900026593; the nICRT group: SCALE-1, ChiCTR2100045104).

Guarantor

Xiangzhi Zhu, Ning Jiang, and Jinjun Ye.

Provenance and peer review

Not commissioned; externally peer-reviewed.

Data availability statement

Research data are stored in an institutional repository and will be shared upon request to the corresponding author.