Treatment strategy after neoadjuvant PD-1 inhibitor combined with chemotherapy for patients with locally advanced esophageal squamous cell carcinoma_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

ZHANG Shifa ^1,2 ,  CAI Haibo ¹ , CHEN Liji ³

1. Department of Thoracic Surgery, The First People's Hospital of Jining, Jining, 272000, Shandong, P. R. China;
2. Institute of Thoracic Surgery, Jining Institute of Medical Science, Jining, 272000, Shandong, P. R. China;
3. Jining Medical University, Jining, 272000, Shandong, P. R. China;

Corresponding author：

CAI Haibo, Email: 13518670801@163.com

Keywords：

Esophageal cancer; surgical treatment; immunotherapy; programmed cell death-1; chemotherapy; prognosis

DOI：

10.7507/1007-4848.202303063

Video：

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Objective To investigate the necessity of further surgery for patients with locally advanced esophageal squamous cell carcinoma following treatment with the programmed cell death-1 (PD-1) inhibitor combined with chemotherapy, and to assess its impact on survival. Methods Patients with stage ⅡA to ⅢB esophageal squamous cell carcinoma who received immunotherapy combined with chemotherapy at our hospital from January 2020 to June 2022 were selected for this study. Based on whether they underwent surgery after receiving PD-1 inhibitor combined with chemotherapy, patients were divided into a surgery group and a non-surgery group. We compared the general clinical data, side effects, clinical complete response rates, progression-free survival (PFS), and overall survival (OS) between the two groups. Results A total of 58 patients were included in the study, comprising 45 males and 13 females, with an average age of (65.5±6.9) years. There were no statistical differences in general clinical data or adverse reactions between the two groups. Univariate analysis revealed that the objective response rate and surgery were significantly associated with PFS (P<0.05). Binary logistic regression analysis showed that surgery was the only independent risk factor for PFS (P=0.003). Kaplan-Meier survival analysis showed that the PFS and OS in the surgery group were significantly higher than those in the non-surgery group (HR=0.13, 95%CI 0.036 to 0.520, P＜0.001; HR=0.17, 95%CI 0.045 to 0.680, P=0.004). Conclusion After treatment with the PD-1 inhibitor combined with chemotherapy, patients with locally advanced esophageal squamous cell carcinoma still require surgical intervention to achieve improved PFS and OS.

Citation： ZHANG Shifa, CAI Haibo, CHEN Liji. Treatment strategy after neoadjuvant PD-1 inhibitor combined with chemotherapy for patients with locally advanced esophageal squamous cell carcinoma. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2025, 32(2): 216-222. doi: 10.7507/1007-4848.202303063 Copy

1.	Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer, 2015, 136(5): E359-E386.
2.	Kamarajah SK, Phillips AW, Hanna GB, et al. Definitive chemoradiotherapy compared to neoadjuvant chemoradiotherapy with esophagectomy for locoregional esophageal cancer: National population-based cohort study. Ann Surg, 2022, 275(3): 526-533.
3.	Kim JH, Kim BJ, Jang HJ, et al. Comparison of the RECIST and EORTC PET criteria in the tumor response assessment: A pooled analysis and review. Cancer Chemother Pharmacol, 2017, 80(4): 729-735.
4.	Schneider BJ, Naidoo J, Santomasso BD, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol, 2021, 20, 39(36): 4073-4126.
5.	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.
6.	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.
7.	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.
8.	Shen L, Kato K, Kim SB, et al. Tislelizumab versus chemotherapy as second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-302): A randomized phase Ⅲ study. J Clin Oncol, 2022, 40(26): 3065-3076.
9.	Kato K, Cho BC, Takahashi M, et al. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol, 2019, 20(11): 1506-1517.
10.	Huang J, Xu J, Chen Y, et al. Camrelizumab versus investigator's choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): A multicentre, randomised, open-label, phase 3 study. Lancet Oncol, 2020, 21(6): 832-842.
11.	Wang ZX, Cui C, Yao J, et al. Toripalimab plus chemotherapy in treatment-naïve, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial. Cancer Cell, 2022, 40(3): 277-288.
12.	Doki Y, Ajani JA, Kato K, et al. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med, 2022, 386(5): 449-462.
13.	Lu Z, Wang J, Shu Y, et al. Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): Multicentre, randomised, double blind, phase 3 trial. BMJ, 2022, 377: e068714.
14.	Luo H, Lu J, Bai Y, et al. Effect of camrelizumab vs placebo added to chemotherapy on survival and progression-free survival in patients with advanced or metastatic esophageal squamous cell carcinoma: The ESCORT-1st randomized clinical trial. JAMA, 2021, 326(10): 916-925.
15.	Chen X, Xu X, Wang D, et al. Neoadjuvant sintilimab and chemotherapy in patients with potentially resectable esophageal squamous cell carcinoma (KEEP-G 03): An open-label, single-arm, phase 2 trial. J Immunother Cancer, 2023, 11(2): e005830.
16.	Liu J, Yang Y, Liu Z, et al. Multicenter, single-arm, phase Ⅱ trial of camrelizumab and chemotherapy as neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma. J Immunother Cancer, 2022, 10(3): e004291.
17.	Yang Y, Zhu L, Cheng Y, et al. Three-arm phase Ⅱ trial comparing camrelizumab plus chemotherapy versus camrelizumab plus chemoradiation versus chemoradiation as preoperative treatment for locally advanced esophageal squamous cell carcinoma (NICE-2 Study). BMC Cancer, 2022, 22(1): 506.
18.	Stahl M, Walz MK, Riera-Knorrenschild J, et al. Preoperative chemotherapy versus chemoradiotherapy in locally advanced adenocarcinomas of the oesophagogastric junction (POET): Long-term results of a controlled randomised trial. Eur J Cancer, 2017, 81: 183-190.
19.	von Döbeln GA, Klevebro F, Jacobsen AB, et al. Neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the esophagus or gastroesophageal junction: Long-term results of a randomized clinical trial. Dis Esophagus, 2019, 32(2): doy078.
20.	Al-Kaabi A, van der Post RS, van der Werf LR, et al. Impact of pathological tumor response after CROSS neoadjuvant chemoradiotherapy followed by surgery on long-term outcome of esophageal cancer: A population-based study. Acta Oncol, 2021, 60(4): 497-504.
21.	Yang H, Liu H, Chen Y, et al. Neoadjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of the esophagus (NEOCRTEC5010): A phase Ⅲ multicenter, randomized, open-label clinical trial. J Clin Oncol, 2018, 36(27): 2796-2803.
22.	Li C, Zhao S, Zheng Y, et al. Preoperative pembrolizumab combined with chemoradiotherapy for oesophageal squamous cell carcinoma (PALACE-1). Eur J Cancer, 2021, 144: 232-241.
23.	Wang H, Tang H, Fang Y, et al. Morbidity and mortality of patients who underwent minimally invasive esophagectomy after neoadjuvant chemoradiotherapy vs neoadjuvant chemotherapy for locally advanced esophageal squamous cell carcinoma: A randomized clinical trial. JAMA Surg, 2021, 156(5): 444-451.
24.	乔宇峰, 于振涛. 食管鳞癌新辅助治疗现状与争议. 中国肿瘤临床, 2019, 46(9): 474-479.Qiao YF, Yu ZT. Current status and controversy of neoadjuvant therapy for esophageal squamous cell carcinoma. Chin J Clin Oncol, 2019, 46(9): 474-479.
25.	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.
26.	Jeong Y, Kim JH, Kim SB, et al. Role of surgical resection in complete responders on FDG-PET after chemoradiotherapy for locally advanced esophageal squamous cell carcinoma. J Surg Oncol, 2014, 109(5): 472-477.
27.	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.

1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer, 2015, 136(5): E359-E386.
2. Kamarajah SK, Phillips AW, Hanna GB, et al. Definitive chemoradiotherapy compared to neoadjuvant chemoradiotherapy with esophagectomy for locoregional esophageal cancer: National population-based cohort study. Ann Surg, 2022, 275(3): 526-533.
3. Kim JH, Kim BJ, Jang HJ, et al. Comparison of the RECIST and EORTC PET criteria in the tumor response assessment: A pooled analysis and review. Cancer Chemother Pharmacol, 2017, 80(4): 729-735.
4. Schneider BJ, Naidoo J, Santomasso BD, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol, 2021, 20, 39(36): 4073-4126.
5. 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.
6. 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.
7. 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.
8. Shen L, Kato K, Kim SB, et al. Tislelizumab versus chemotherapy as second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-302): A randomized phase Ⅲ study. J Clin Oncol, 2022, 40(26): 3065-3076.
9. Kato K, Cho BC, Takahashi M, et al. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol, 2019, 20(11): 1506-1517.
10. Huang J, Xu J, Chen Y, et al. Camrelizumab versus investigator's choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): A multicentre, randomised, open-label, phase 3 study. Lancet Oncol, 2020, 21(6): 832-842.
11. Wang ZX, Cui C, Yao J, et al. Toripalimab plus chemotherapy in treatment-naïve, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial. Cancer Cell, 2022, 40(3): 277-288.
12. Doki Y, Ajani JA, Kato K, et al. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med, 2022, 386(5): 449-462.
13. Lu Z, Wang J, Shu Y, et al. Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): Multicentre, randomised, double blind, phase 3 trial. BMJ, 2022, 377: e068714.
14. Luo H, Lu J, Bai Y, et al. Effect of camrelizumab vs placebo added to chemotherapy on survival and progression-free survival in patients with advanced or metastatic esophageal squamous cell carcinoma: The ESCORT-1st randomized clinical trial. JAMA, 2021, 326(10): 916-925.
15. Chen X, Xu X, Wang D, et al. Neoadjuvant sintilimab and chemotherapy in patients with potentially resectable esophageal squamous cell carcinoma (KEEP-G 03): An open-label, single-arm, phase 2 trial. J Immunother Cancer, 2023, 11(2): e005830.
16. Liu J, Yang Y, Liu Z, et al. Multicenter, single-arm, phase Ⅱ trial of camrelizumab and chemotherapy as neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma. J Immunother Cancer, 2022, 10(3): e004291.
17. Yang Y, Zhu L, Cheng Y, et al. Three-arm phase Ⅱ trial comparing camrelizumab plus chemotherapy versus camrelizumab plus chemoradiation versus chemoradiation as preoperative treatment for locally advanced esophageal squamous cell carcinoma (NICE-2 Study). BMC Cancer, 2022, 22(1): 506.
18. Stahl M, Walz MK, Riera-Knorrenschild J, et al. Preoperative chemotherapy versus chemoradiotherapy in locally advanced adenocarcinomas of the oesophagogastric junction (POET): Long-term results of a controlled randomised trial. Eur J Cancer, 2017, 81: 183-190.
19. von Döbeln GA, Klevebro F, Jacobsen AB, et al. Neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the esophagus or gastroesophageal junction: Long-term results of a randomized clinical trial. Dis Esophagus, 2019, 32(2): doy078.
20. Al-Kaabi A, van der Post RS, van der Werf LR, et al. Impact of pathological tumor response after CROSS neoadjuvant chemoradiotherapy followed by surgery on long-term outcome of esophageal cancer: A population-based study. Acta Oncol, 2021, 60(4): 497-504.
21. Yang H, Liu H, Chen Y, et al. Neoadjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of the esophagus (NEOCRTEC5010): A phase Ⅲ multicenter, randomized, open-label clinical trial. J Clin Oncol, 2018, 36(27): 2796-2803.
22. Li C, Zhao S, Zheng Y, et al. Preoperative pembrolizumab combined with chemoradiotherapy for oesophageal squamous cell carcinoma (PALACE-1). Eur J Cancer, 2021, 144: 232-241.
23. Wang H, Tang H, Fang Y, et al. Morbidity and mortality of patients who underwent minimally invasive esophagectomy after neoadjuvant chemoradiotherapy vs neoadjuvant chemotherapy for locally advanced esophageal squamous cell carcinoma: A randomized clinical trial. JAMA Surg, 2021, 156(5): 444-451.
24. 乔宇峰, 于振涛. 食管鳞癌新辅助治疗现状与争议. 中国肿瘤临床, 2019, 46(9): 474-479.Qiao YF, Yu ZT. Current status and controversy of neoadjuvant therapy for esophageal squamous cell carcinoma. Chin J Clin Oncol, 2019, 46(9): 474-479.
25. 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.
26. Jeong Y, Kim JH, Kim SB, et al. Role of surgical resection in complete responders on FDG-PET after chemoradiotherapy for locally advanced esophageal squamous cell carcinoma. J Surg Oncol, 2014, 109(5): 472-477.
27. 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.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Treatment strategy after neoadjuvant PD-1 inhibitor combined with chemotherapy for patients with locally advanced esophageal squamous cell carcinoma

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