From CROSS to SANO: Evidence-based breakthroughs and clinical practice challenges in organ-preservation strategies for esophageal cancer in the era of neoadjuvant therapy_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

 LI Hui

Department of Thoracic Surgery, Hebei Yanda Hospital, Langfang, 065201, Hebei, P. R. China;

Corresponding author：

LI Hui, Email: huilee@vip.sina.com

Keywords：

Esophageal cancer organ preservation; neoadjuvant chemoradiotherapy; clinical complete response; active surveillance strategy; salvage surgery

DOI：

10.7507/1007-4848.202508031

Video：

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Organ preservation after neoadjuvant therapy for esophageal cancer has gained significant attention. While the CROSS trial established neoadjuvant chemoradiotherapy (nCRT) followed by surgery as standard care, approximately 30% of patients achieve pathological complete response (pCR), prompting exploration of active surveillance (AS). The landmark SANO phase Ⅲ trial (2025) demonstrated non-inferior 2-year overall survival (74% AS vs. 71% surgery), with 31% of patients avoiding surgery. Multimodal assessment (endoscopic deep biopsy+EUS+PET-CT) reduced residual disease misdiagnosis to 10%. The Asian-led NEEDS trial is evaluating definitive chemoradiotherapy with salvage surgery. Although immunotherapy boosts pCR rates to 40%-55%, challenges persist, including 8%-12% false-negative cCR assessments, limited long-term data, and East-West histological disparities. The 2024 NCCN guidelines conditionally recommend AS (Category 2B, prioritized for squamous cell carcinoma), emphasizing centralized implementation. Future directions involve ctDNA and radiomics for risk stratification to advance precision organ-preserving strategies.

1.	Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263.
2.	Biere SS, van Berge Henegouwen MI, Maas KW, et al. Minimally invasive versus open oesophagectomy for patients with oesophageal cancer: a multicentre, open-label, randomised controlled trial. Lancet, 2012, 379(9829): 1887-1892.
3.	van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med, 2012, 366(22): 2074-2084.
4.	Shapiro J, van Lanschot JJB, Hulshof MCCM, et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol, 2015, 16(9): 1090-1098.
5.	Yang H, Liu H, Chen Y, et al. Long-term efficacy of neoadjuvant chemoradiotherapy plus surgery for the treatment of locally advanced esophageal squamous cell carcinoma: the NEOCRTEC5010 randomized clinical trial. JAMA Surg, 2021, 156(8): 721-729.
6.	Nilsson K, Klevebro F, Sunde B, et al. Oncological outcomes of standard versus prolonged time to surgery after neoadjuvant chemoradiotherapy for oesophageal cancer in the multicentre, randomised, controlled NeoRes II trial. Ann Oncol, 2023, 34(11): 1015-1024.
7.	Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet, 2021, 398(10302): 759-771.
8.	Kato K, Doki Y, Ogata T, et al. First-line nivolumab plus ipilimumab or chemotherapy versus chemotherapy alone in advanced esophageal squamous cell carcinoma: a Japanese subgroup analysis of open-label, phase 3 trial (CheckMate 648/ONO-4538-50). Esophagus, 2023, 20(2): 291-301.
9.	Kojima T, Shah MA, Muro K, et al. Randomized phase Ⅲ KEYNOTE-181 study of pembrolizumab versus chemotherapy in advanced esophageal cancer. J Clin Oncol, 2020, 38(35): 4138-4148.
10.	Noordman BJ, Spaander MCW, Valkema R, et al. Detection of residual disease after neoadjuvant chemoradiotherapy for oesophageal cancer (preSANO): a prospective multicentre, diagnostic cohort study. Lancet Oncol, 2018, 19(7): 965-974.
11.	Yang Y, Liu Z, Wong I, et al. Detecting residual disease after neoadjuvant chemoradiotherapy for oesophageal squamous cell carcinoma: the prospective multicentre preSINO trial. Br J Surg, 2025, 112(2): znaf004.
12.	Azad TD, Chaudhuri AA, Fang P, et al. Circulating tumor DNA analysis for detection of minimal residual disease after chemoradiotherapy for localized esophageal cancer. Gastroenterology, 2020, 158(3): 494-505.
13.	van der Wilk BJ, Eyck BM, Lagarde SM, et al. Neoadjuvant chemoradiotherapy followed by active surveillance versus standard surgery for oesophageal cancer (SANO trial): a multicentre, stepped-wedge, cluster-randomised, non-inferiority, phase 3 trial. Lancet Oncol, 2025, 26(4): 425-436.
14.	van der Zijden CJ, Lagarde SM, Hermus M, et al. A prospective cohort study on active surveillance after neoadjuvant chemoradiotherapy for esophageal cancer: protocol of Surgery As Needed for Oesophageal cancer-2. BMC Cancer, 2023, 23(1): 327.
15.	Bedenne L, Michel P, Bouché O, et al. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol, 2007, 25(10): 1160-1168.
16.	Nilsson M, Olafsdottir H, Alexandersson von Döbeln G, et al. Neoadjuvant chemoradiotherapy and surgery for esophageal squamous cell carcinoma versus definitive chemoradiotherapy with salvage surgery as needed: the study protocol for the randomized controlled NEEDS trial. Front Oncol, 2022, 12: 917961.
17.	van der Wilk BJ, Eyck BM, Hofstetter WL, et al. Chemoradiotherapy followed by active surveillance versus standard esophagectomy for esophageal cancer: a systematic review and individual patient data meta-analysis. Ann Surg, 2022, 275(3): 467-476.
18.	Qian D, Chen X, Shang X, et al. Definitive chemoradiotherapy versus neoadjuvant chemoradiotherapy followed by surgery in patients with locally advanced esophageal squamous cell carcinoma who achieved clinical complete response when induction chemoradiation finished: a phase Ⅱ random. Radiother Oncol, 2022, 174: 1-7.
19.	National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN Guidelines®): esophageal and esophagogastric junction cancers. Version 3.2025.
20.	Makazu M, Kato K, Takisawa H, et al. Feasibility of endoscopic mucosal resection as salvage treatment for patients with local failure after definitive chemoradiotherapy for stage ⅠB, Ⅱ, and Ⅲ esophageal squamous cell cancer. Dis Esophagus, 2014, 27(1): 42-49.
21.	Booka E, Takeuchi H, Kikuchi H, et al. Recent advances in thoracoscopic esophagectomy for esophageal cancer. Asian J Endosc Surg, 2019, 12(1): 19-29.
22.	Markar SR, Van Berge Henegouwen M, Bruns C, et al. Does the SANO trial really move us toward organ preservation for esophageal cancer? Dis Esophagus, 2025, 38(3): doaf049.
23.	de Gouw DJJM, Klarenbeek BR, Driessen M, et al. Detecting pathological complete response in esophageal cancer after neoadjuvant therapy based on imaging techniques: a diagnostic systematic review and meta-analysis. J Thorac Oncol, 2019, 14(7): 1156-1171.
24.	National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN Guidelines®): esophageal and esophagogastric junction cancers. Version 2.2024.
25.	中国临床肿瘤学会指南工作委员会. CSCO食管癌诊疗指南2023. 北京: 人民卫生出版社, 2023.Chinese Society of Clinical Oncology (CSCO) Guidelines Working Committee. CSCO guidelines for the diagnosis and treatment of esophageal cancer 2023. Beijing: People's Medical Publishing House, 2023.
26.	Liu G, Chen T, Zhang X, et al. Nomogram for predicting pathologic complete response to neoadjuvant chemoradiotherapy in patients with esophageal squamous cell carcinoma. Cancer Med, 2024, 13(5): e7075.
27.	Hermus M, van der Zijden CJ, Wijnhoven BPL, et al. Patients' preferences towards decision counseling for active surveillance after neoadjuvant chemoradiotherapy for esophageal cancer. Ann Surg Oncol, 2024, 31(3): 1562-1567.
28.	Gao X, Xu N, Li Z, et al. Safety and antitumour activity of cadonilimab, an anti-PD-1/CTLA-4 bispecific antibody, for patients with advanced solid tumours (COMPASSION-03): a multicentre, open-label, phase 1b/2 trial. Lancet Oncol, 2023, 24(10): 1134-1146.

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263.
2. Biere SS, van Berge Henegouwen MI, Maas KW, et al. Minimally invasive versus open oesophagectomy for patients with oesophageal cancer: a multicentre, open-label, randomised controlled trial. Lancet, 2012, 379(9829): 1887-1892.
3. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med, 2012, 366(22): 2074-2084.
4. Shapiro J, van Lanschot JJB, Hulshof MCCM, et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol, 2015, 16(9): 1090-1098.
5. Yang H, Liu H, Chen Y, et al. Long-term efficacy of neoadjuvant chemoradiotherapy plus surgery for the treatment of locally advanced esophageal squamous cell carcinoma: the NEOCRTEC5010 randomized clinical trial. JAMA Surg, 2021, 156(8): 721-729.
6. Nilsson K, Klevebro F, Sunde B, et al. Oncological outcomes of standard versus prolonged time to surgery after neoadjuvant chemoradiotherapy for oesophageal cancer in the multicentre, randomised, controlled NeoRes II trial. Ann Oncol, 2023, 34(11): 1015-1024.
7. Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet, 2021, 398(10302): 759-771.
8. Kato K, Doki Y, Ogata T, et al. First-line nivolumab plus ipilimumab or chemotherapy versus chemotherapy alone in advanced esophageal squamous cell carcinoma: a Japanese subgroup analysis of open-label, phase 3 trial (CheckMate 648/ONO-4538-50). Esophagus, 2023, 20(2): 291-301.
9. Kojima T, Shah MA, Muro K, et al. Randomized phase Ⅲ KEYNOTE-181 study of pembrolizumab versus chemotherapy in advanced esophageal cancer. J Clin Oncol, 2020, 38(35): 4138-4148.
10. Noordman BJ, Spaander MCW, Valkema R, et al. Detection of residual disease after neoadjuvant chemoradiotherapy for oesophageal cancer (preSANO): a prospective multicentre, diagnostic cohort study. Lancet Oncol, 2018, 19(7): 965-974.
11. Yang Y, Liu Z, Wong I, et al. Detecting residual disease after neoadjuvant chemoradiotherapy for oesophageal squamous cell carcinoma: the prospective multicentre preSINO trial. Br J Surg, 2025, 112(2): znaf004.
12. Azad TD, Chaudhuri AA, Fang P, et al. Circulating tumor DNA analysis for detection of minimal residual disease after chemoradiotherapy for localized esophageal cancer. Gastroenterology, 2020, 158(3): 494-505.
13. van der Wilk BJ, Eyck BM, Lagarde SM, et al. Neoadjuvant chemoradiotherapy followed by active surveillance versus standard surgery for oesophageal cancer (SANO trial): a multicentre, stepped-wedge, cluster-randomised, non-inferiority, phase 3 trial. Lancet Oncol, 2025, 26(4): 425-436.
14. van der Zijden CJ, Lagarde SM, Hermus M, et al. A prospective cohort study on active surveillance after neoadjuvant chemoradiotherapy for esophageal cancer: protocol of Surgery As Needed for Oesophageal cancer-2. BMC Cancer, 2023, 23(1): 327.
15. Bedenne L, Michel P, Bouché O, et al. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol, 2007, 25(10): 1160-1168.
16. Nilsson M, Olafsdottir H, Alexandersson von Döbeln G, et al. Neoadjuvant chemoradiotherapy and surgery for esophageal squamous cell carcinoma versus definitive chemoradiotherapy with salvage surgery as needed: the study protocol for the randomized controlled NEEDS trial. Front Oncol, 2022, 12: 917961.
17. van der Wilk BJ, Eyck BM, Hofstetter WL, et al. Chemoradiotherapy followed by active surveillance versus standard esophagectomy for esophageal cancer: a systematic review and individual patient data meta-analysis. Ann Surg, 2022, 275(3): 467-476.
18. Qian D, Chen X, Shang X, et al. Definitive chemoradiotherapy versus neoadjuvant chemoradiotherapy followed by surgery in patients with locally advanced esophageal squamous cell carcinoma who achieved clinical complete response when induction chemoradiation finished: a phase Ⅱ random. Radiother Oncol, 2022, 174: 1-7.
19. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN Guidelines®): esophageal and esophagogastric junction cancers. Version 3.2025.
20. Makazu M, Kato K, Takisawa H, et al. Feasibility of endoscopic mucosal resection as salvage treatment for patients with local failure after definitive chemoradiotherapy for stage ⅠB, Ⅱ, and Ⅲ esophageal squamous cell cancer. Dis Esophagus, 2014, 27(1): 42-49.
21. Booka E, Takeuchi H, Kikuchi H, et al. Recent advances in thoracoscopic esophagectomy for esophageal cancer. Asian J Endosc Surg, 2019, 12(1): 19-29.
22. Markar SR, Van Berge Henegouwen M, Bruns C, et al. Does the SANO trial really move us toward organ preservation for esophageal cancer? Dis Esophagus, 2025, 38(3): doaf049.
23. de Gouw DJJM, Klarenbeek BR, Driessen M, et al. Detecting pathological complete response in esophageal cancer after neoadjuvant therapy based on imaging techniques: a diagnostic systematic review and meta-analysis. J Thorac Oncol, 2019, 14(7): 1156-1171.
24. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN Guidelines®): esophageal and esophagogastric junction cancers. Version 2.2024.
25. 中国临床肿瘤学会指南工作委员会. CSCO食管癌诊疗指南2023. 北京: 人民卫生出版社, 2023.Chinese Society of Clinical Oncology (CSCO) Guidelines Working Committee. CSCO guidelines for the diagnosis and treatment of esophageal cancer 2023. Beijing: People's Medical Publishing House, 2023.
26. Liu G, Chen T, Zhang X, et al. Nomogram for predicting pathologic complete response to neoadjuvant chemoradiotherapy in patients with esophageal squamous cell carcinoma. Cancer Med, 2024, 13(5): e7075.
27. Hermus M, van der Zijden CJ, Wijnhoven BPL, et al. Patients' preferences towards decision counseling for active surveillance after neoadjuvant chemoradiotherapy for esophageal cancer. Ann Surg Oncol, 2024, 31(3): 1562-1567.
28. Gao X, Xu N, Li Z, et al. Safety and antitumour activity of cadonilimab, an anti-PD-1/CTLA-4 bispecific antibody, for patients with advanced solid tumours (COMPASSION-03): a multicentre, open-label, phase 1b/2 trial. Lancet Oncol, 2023, 24(10): 1134-1146.

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