Advances in total neoadjuvant therapy strategies for esophageal and esophagogastric junction cancers

doi:10.3877/cma.j.issn.2095-8773.2025.03.07

Abstract

Abstract:

Esophageal cancer and esophagogastric junction cancer are highly prevalent malignant tumors in China, and most patients are diagnosed at an advanced stage. Neoadjuvant therapy has become the standard treatment for locally advanced patients. However, although traditional neoadjuvant chemoradiotherapy (nCRT) can improve the surgical resection rate, the distant metastasis rate remains high, indicating that the treatment strategy needs further optimization. Total neoadjuvant therapy (TNT) overcomes the drug resistance caused by tumor heterogeneity from the spatiotemporal dimension through early intensive systemic therapy, multidrug sequential combination, and dynamic adaptive adjustment, showing good prospects in both esophageal adenocarcinoma and squamous cell carcinoma. Existing studies have shown that the TNT strategy can improve the R0 resection rate in esophageal adenocarcinoma [for example, the pathological complete response rate (pCR) of the FLOT regimen (docetaxel + oxaliplatin + leucovorin + 5-fluorouracil) reaches 20%], and nCRT combined with immunotherapy (such as atezolizumab) can further improve survival [the 2-year overall survival (OS) rate in the PERFECT trial reaches 92%]. In esophageal squamous cell carcinoma, immunotherapy combined with nCRT significantly increases the pCR rate (55.6% in the PALACE-1 study and 63.2% in the CRIS study), and specific biomarkers (such as TCF-1⁺ T cells) may predict therapeutic efficacy. However, the toxicity management of TNT (such as lymphopenia) and the optimal treatment sequence still need further optimization. Future research directions include: developing a dynamic monitoring system for ctDNA to guide individualized treatment; exploring innovative combinations such as dual immunotherapy blockade and antibody-drug conjugates; and verifying long-term survival benefits through phase Ⅲ clinical trials (such as KEYNOTE-975 and EA2174). Multidisciplinary collaboration and precision immunotherapy will drive the innovation of neoadjuvant therapy for esophageal cancer.

Key words: Esophageal neoplasms, Gastroesophageal junction tumors, Total neoadjuvant therapy, Pathologic complete response, Prognosis

Xiaozheng Kang, Ruixiang Zhang, Zhen Wang, Xiankai Chen, Xiaobin Shang, Yong Li, Jianjun Qin, Yin Li. Advances in total neoadjuvant therapy strategies for esophageal and esophagogastric junction cancers[J]. Chinese Journal of Thoracic Surgery(Electronic Edition), 2025, 12(03): 176-184.

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References 33

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研究/作者	研究类型	病例数	治疗方案	生存结果	其他结局指标
NeoFLOT^[12]	前瞻性单臂研究	50	FLOT方案（6周期）	中位DFS：32.9个月；1年OS率：79.3%	R0切除率：86%；pCR率：20%；TRG 1a/b级：40%；发热性中性粒细胞减少：1.7%；≥3级中性粒细胞减少：29.3%；剂量调整：43.1%
Wo等^[13]	前瞻性单臂研究	25	nFOLFIRINOX（8周期）+新辅助放化疗	2年PFS率：55%；2年OS率：72%	TNT完成率：88%；手术切除率：80%；pCR率：35%；≥4级毒性：80%（淋巴细胞减少）
Dunne等^[14]	前瞻性单臂研究	41	FOLFOX（3周期）+CROSS方案	中位RFS：3.1年；2年RFS率：71.5%	95%完成新辅助化疗；98%完成放化疗；R0切除率：97%；pCR率：22%
Shi等^[15]	前瞻性单臂研究	28	放化疗（45 Gy）+SOX方案（6周期）	3年OS率：63%（手术组）	R0切除率：100%；pCR率：35.7%
Ho等^[16]	回顾性对照研究	580	诱导化疗+新辅助放化疗比单纯新辅助放化疗	中位OS：3.38年比2.45年（P＝0.001）	淋巴结阴性率：21.2%比16.9%（无显著差异）
Carr等^[17]	回顾性对照研究	451	诱导FOLFOX+新辅助放化疗比单纯新辅助放化疗	2年DFS率：68%比44%（P<0.001）	pCR率：33%比22%（无显著差异）；术后并发症无显著差异
PERFECT^[18]	前瞻性单臂Ⅱ期临床研究	40	阿替利珠单抗+CROSS方案	2年OS率：92%（IFN-γ高表达亚组）	pCR率：25%；IFN-γ特征基因可预测疗效
Uboha研究^[19]	前瞻性单臂Ⅰ/Ⅱ期临床研究	22	阿维鲁单抗+同步放化疗	1年RFS率：71%；1年OS率：81%	pCR率：26%；鳞癌67%比腺癌19%；versican蛋白水解状态可预测疗效
Ko等^[20]	前瞻性单臂Ⅱ期临床研究	33	Sotigalimab（CD40激动剂）+放化疗	未报道	pCR率：37.9%；食管鳞癌pCR率达60%；增强树突细胞/T细胞免疫应答

研究/作者	研究类型	病例数	治疗方案	生存结果	其他结局指标
NeoFLOT^[12]	前瞻性单臂研究	50	FLOT方案（6周期）	中位DFS：32.9个月；1年OS率：79.3%	R0切除率：86%；pCR率：20%；TRG 1a/b级：40%；发热性中性粒细胞减少：1.7%；≥3级中性粒细胞减少：29.3%；剂量调整：43.1%
Wo等^[13]	前瞻性单臂研究	25	nFOLFIRINOX（8周期）+新辅助放化疗	2年PFS率：55%；2年OS率：72%	TNT完成率：88%；手术切除率：80%；pCR率：35%；≥4级毒性：80%（淋巴细胞减少）
Dunne等^[14]	前瞻性单臂研究	41	FOLFOX（3周期）+CROSS方案	中位RFS：3.1年；2年RFS率：71.5%	95%完成新辅助化疗；98%完成放化疗；R0切除率：97%；pCR率：22%
Shi等^[15]	前瞻性单臂研究	28	放化疗（45 Gy）+SOX方案（6周期）	3年OS率：63%（手术组）	R0切除率：100%；pCR率：35.7%
Ho等^[16]	回顾性对照研究	580	诱导化疗+新辅助放化疗比单纯新辅助放化疗	中位OS：3.38年比2.45年（P＝0.001）	淋巴结阴性率：21.2%比16.9%（无显著差异）
Carr等^[17]	回顾性对照研究	451	诱导FOLFOX+新辅助放化疗比单纯新辅助放化疗	2年DFS率：68%比44%（P<0.001）	pCR率：33%比22%（无显著差异）；术后并发症无显著差异
PERFECT^[18]	前瞻性单臂Ⅱ期临床研究	40	阿替利珠单抗+CROSS方案	2年OS率：92%（IFN-γ高表达亚组）	pCR率：25%；IFN-γ特征基因可预测疗效
Uboha研究^[19]	前瞻性单臂Ⅰ/Ⅱ期临床研究	22	阿维鲁单抗+同步放化疗	1年RFS率：71%；1年OS率：81%	pCR率：26%；鳞癌67%比腺癌19%；versican蛋白水解状态可预测疗效
Ko等^[20]	前瞻性单臂Ⅱ期临床研究	33	Sotigalimab（CD40激动剂）+放化疗	未报道	pCR率：37.9%；食管鳞癌pCR率达60%；增强树突细胞/T细胞免疫应答

研究/作者	研究类型	病例数	治疗方案	生存结果	其他结局指标
Peng等^[22]	前瞻性Ⅱ期	87（非CCR患者）	序贯化疗免疫比直接手术	12个月PFS率：95.6%比77.3%	pCR率：40.7%比18.1%（P＝0.024）；MPR率：51.8%比33.3%；主要毒副反应：淋巴细胞减少（97.7%）
CRIS^[23]	前瞻性单臂Ⅰb期	35（19例手术）	新辅助放化疗+替雷利珠单抗（2周期）	未报道	pCR率：63.2%；MPR率：78.9%；R0切除率：94.7%；≥3级毒副反应：白细胞减少（33.3%）
Xu等^[24]	前瞻性单臂Ⅰb期	21（19例可评估）	新辅助放化疗+围手术期特瑞普利单抗	非MPR患者中位DFS：12.2个月（P<0.001比MPR）	MPR率：78.9%；pCR率：47.4%；≥3级毒副反应：淋巴细胞减少（66.7%）
PALACE-1^[25]	前瞻性单臂Ⅰb期	20（18手术）	新辅助放化疗+帕博利珠单抗（2周期）	中位随访6.6个月无复发	pCR率：55.6%；R0切除率：94%；≥3级毒副反应：65%（淋巴细胞减少60%）；术后并发症：肺炎（22%）
NEOCRTEC1901^[26]	前瞻性单臂Ⅱ期	44（42例手术）	新辅助放化疗+特瑞普利单抗（2周期）	2年OS率：81.5%；2年DFS率：79.2%	pCR率：50%；R0切除率：98%；≥3级毒副反应：20%（白细胞减少9%）；术后并发症：吻合口瘘（12%）

研究/作者	研究类型	病例数	治疗方案	生存结果	其他结局指标
Peng等^[22]	前瞻性Ⅱ期	87（非CCR患者）	序贯化疗免疫比直接手术	12个月PFS率：95.6%比77.3%	pCR率：40.7%比18.1%（P＝0.024）；MPR率：51.8%比33.3%；主要毒副反应：淋巴细胞减少（97.7%）
CRIS^[23]	前瞻性单臂Ⅰb期	35（19例手术）	新辅助放化疗+替雷利珠单抗（2周期）	未报道	pCR率：63.2%；MPR率：78.9%；R0切除率：94.7%；≥3级毒副反应：白细胞减少（33.3%）
Xu等^[24]	前瞻性单臂Ⅰb期	21（19例可评估）	新辅助放化疗+围手术期特瑞普利单抗	非MPR患者中位DFS：12.2个月（P<0.001比MPR）	MPR率：78.9%；pCR率：47.4%；≥3级毒副反应：淋巴细胞减少（66.7%）
PALACE-1^[25]	前瞻性单臂Ⅰb期	20（18手术）	新辅助放化疗+帕博利珠单抗（2周期）	中位随访6.6个月无复发	pCR率：55.6%；R0切除率：94%；≥3级毒副反应：65%（淋巴细胞减少60%）；术后并发症：肺炎（22%）
NEOCRTEC1901^[26]	前瞻性单臂Ⅱ期	44（42例手术）	新辅助放化疗+特瑞普利单抗（2周期）	2年OS率：81.5%；2年DFS率：79.2%	pCR率：50%；R0切除率：98%；≥3级毒副反应：20%（白细胞减少9%）；术后并发症：吻合口瘘（12%）

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