Analysis of short-term efficacy and safety of neoadjuvant sintilimab plus chemotherapy for locally advanced resectable esophageal squamous cell carcinoma_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

CHEN Liji ¹ , HUANG Junjun ³ , MA Hongmei ² , ZHANG Shifa ² , YANG Dongbao ¹ , SUN Jiuhe ² , LIU Hongfeng ² , ZHONG Kaize ² ,  CAI Haibo ²

1. Jining Medical University, Jining, 272000, Shandong, P. R. China;
2. Department of Thoracic Surgery, The First People's Hospital of Jining, Jining, 272000, Shandong, P. R. China;
3. Department of Thoracic Surgery, Huzhou Central Hospital, Huzhou, 313000, Zhejiang, P. R. China;

Corresponding author：

CAI Haibo, Email: 13518670801@163.com

Keywords：

Esophageal squamous cell carcinoma; sintilimab; neoadjuvant therapy; PD-1 inhibitor; pathological complete response; major pathologic response

DOI：

10.7507/1007-4848.202406041

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To observe the short-term efficacy and safety of neoadjuvant sintilimab combined with chemotherapy in the treatment of patients with locally advanced resectable esophageal squamous cell carcinoma (ESCC). Methods Clinical data were collected from patients with locally advanced resectable ESCC who received neoadjuvant immunotherapy combined with chemotherapy followed by surgical treatment at the Thoracic Surgery Department of Jining First People's Hospital from April 2020 to April 2022. The endpoints included major pathological response (MPR), pathological complete response (pCR), R0 resection rate, safety, and postoperative survival. Results A total of 43 patients with ESCC who received at least one cycle of neoadjuvant immunotherapy before surgery were included. Among them, there were 31 males and 12 females, aged from 46 to 77 years, with a median age of 65 years. All patients successfully completed the surgery without any surgical delays. The pCR rate was 14.0% (6/43), the MPR rate was 58.1% (25/43), and the R0 resection rate was 97.7% (42/43). Patients exhibited reliable safety during neoadjuvant therapy and postoperatively. The 2-year overall survival (OS) and disease-free survival (DFS) rates were 90.7% and 81.4%, respectively. Kaplan-Meier survival analysis and log-rank test revealed lower recurrence rates and better survival in the MPR group compared to the non-MPR group. Conclusion The combination of neoadjuvant sintilimab and chemotherapy in the treatment of patients with locally advanced resectable ESCC has demonstrated significant clinical efficacy, while also being safe and reliable.

1.	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
2.	Cao W, Chen HD, Yu YW, et al. Changing profiles of cancer burden worldwide and in China: A secondary analysis of the global cancer statistics 2020. Chin Med J (Engl), 2021, 134(7): 783-791.
3.	Lin Y, Totsuka Y, He Y, et al. Epidemiology of esophageal cancer in Japan and China. J Epidemiol, 2013, 23(4): 233-242.
4.	He Y, Li D, Shan B, et al. Incidence and mortality of esophagus cancer in China, 2008—2012. Chin J Cancer Res, 2019, 31(3): 426-434.
5.	Guo X, Mao T, Gu Z, et al. Clinical study on postoperative recurrence in patients with pN1 esophageal squamous cell carcinoma. Thorac Cancer, 2015, 6(2): 146-150.
6.	Ando N, Kato H, Igaki H, et al. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol, 2012, 19(1): 68-74.
7.	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.
8.	Eyck BM, van Lanschot JJB, Hulshof MCCM, et al. Ten-year outcome of neoadjuvant chemoradiotherapy plus surgery for esophageal cancer: The randomized controlled CROSS trial. J Clin Oncol, 2021, 39(18): 1995-2004.
9.	Leng X, He W, Yang H, et al. Prognostic impact of postoperative lymph node metastases after neoadjuvant chemoradiotherapy for locally advanced squamous cell carcinoma of esophagus: From the results of NEOCRTEC5010, a randomized multicenter study. Ann Surg, 2021, 274(6): e1022-e1029.
10.	Moujaess E, Haddad FG, Eid R, et al. The emerging use of immune checkpoint blockade in the adjuvant setting for solid tumors: A review. Immunotherapy, 2019, 11(16): 1409-1422.
11.	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.
12.	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.
13.	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.
14.	Park SY, Hong MH, Kim HR, et al. The feasibility and safety of radical esophagectomy in patients receiving neoadjuvant chemoradiotherapy with pembrolizumab for esophageal squamous cell carcinoma. J Thorac Dis, 2020, 12(11): 6426-6434.
15.	Shang X, Zhao G, Liang F, et al. Safety and effectiveness of pembrolizumab combined with paclitaxel and cisplatin as neoadjuvant therapy followed by surgery for locally advanced resectable (stage Ⅲ) esophageal squamous cell carcinoma: A study protocol for a prospective, single-arm, single-center, open-label, phase-Ⅱ trial (Keystone-001). Ann Transl Med, 2022, 10(4): 229.
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.	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.
18.	Samson P, Robinson C, Bradley J, et al. Neoadjuvant chemotherapy versus chemoradiation prior to esophagectomy: Impact on rate of complete pathologic response and survival in esophageal cancer patients. J Thorac Oncol, 2016, 11(12): 2227-2237.
19.	Klevebro F, Alexandersson von Döbeln G, Wang N, et al. A randomized clinical trial of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the oesophagus or gastro-oesophageal junction. Ann Oncol, 2016, 27(4): 660-667.
20.	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.
21.	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.
22.	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.
23.	Lv H, Tian Y, Li J, et al. Neoadjuvant sintilimab plus chemotherapy in resectable locally advanced esophageal squamous cell carcinoma. Front Oncol, 2022 Apr 29: 12: 864533.
24.	Liu J, Li J, Lin W, et al. Neoadjuvant camrelizumab plus chemotherapy for resectable, locally advanced esophageal squamous cell carcinoma (NIC-ESCC2019): A multicenter, phase 2 study. Int J Cancer, 2022, 151(1): 128-137.
25.	Yang W, Xing X, Yeung SJ, et al. Neoadjuvant programmed cell death 1 blockade combined with chemotherapy for resectable esophageal squamous cell carcinoma. J Immunother Cancer, 2022, 10(1): e003497.
26.	Xing W, Zhao L, Zheng Y, et al. The sequence of chemotherapy and toripalimab might influence the efficacy of neoadjuvant chemoimmunotherapy in locally advanced esophageal squamous cell cancer—A phase Ⅱ study. Front Immunol, 2021, 12: 772450.
27.	Wu Z, Zheng Q, Chen H, et al. Efficacy and safety of neoadjuvant chemotherapy and immunotherapy in locally resectable advanced esophageal squamous cell carcinoma. J Thorac Dis, 2021, 13(6): 3518-3528.
28.	He W, Leng X, Mao T, et al. Toripalimab plus paclitaxel and carboplatin as neoadjuvant therapy in locally advanced resectable esophageal squamous cell carcinoma. Oncologist, 2022, 27(1): e18-e28.18-28.
29.	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.
30.	Sihag S, Ku GY, Tan KS, et al. Safety and feasibility of esophagectomy following combined immunotherapy and chemoradiotherapy for esophageal cancer. J Thorac Cardiovasc Surg, 2021, 161(3): 836-843.
31.	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: 232-241.144-232.
32.	van den Ende T, de Clercq NC, van Berge Henegouwen MI, et al. Neoadjuvant chemoradiotherapy combined with atezolizumab for resectable esophageal adenocarcinoma: A single-arm phase Ⅱ feasibility trial (PERFECT). Clin Cancer Res, 2021, 27(12): 3351-3359.
33.	Yang G, Su X, Huang Y, et al. Intensive cycles of neoadjuvant camrelizumab combined with chemotherapy in locally advanced esophageal squamous cell carcinoma: A single-arm, phase Ⅱtrial. J Transl Med, 2023, 21(1): 411.
34.	Blakely CM, McCoach CE. Role of MPR as an early signal for efficacy in neoadjuvant studies. Clin Cancer Res, 2020, 26(14): 3499-3500.
35.	Yang Y, Liu J, Liu Z, et al. Two-year outcomes of clinical N2-3 esophageal squamous cell carcinoma after neoadjuvant chemotherapy and immunotherapy from the phase 2 NICE study. J Thorac Cardiovasc Surg, 2024, 167(3): 838-847.

1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
2. Cao W, Chen HD, Yu YW, et al. Changing profiles of cancer burden worldwide and in China: A secondary analysis of the global cancer statistics 2020. Chin Med J (Engl), 2021, 134(7): 783-791.
3. Lin Y, Totsuka Y, He Y, et al. Epidemiology of esophageal cancer in Japan and China. J Epidemiol, 2013, 23(4): 233-242.
4. He Y, Li D, Shan B, et al. Incidence and mortality of esophagus cancer in China, 2008—2012. Chin J Cancer Res, 2019, 31(3): 426-434.
5. Guo X, Mao T, Gu Z, et al. Clinical study on postoperative recurrence in patients with pN1 esophageal squamous cell carcinoma. Thorac Cancer, 2015, 6(2): 146-150.
6. Ando N, Kato H, Igaki H, et al. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol, 2012, 19(1): 68-74.
7. 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.
8. Eyck BM, van Lanschot JJB, Hulshof MCCM, et al. Ten-year outcome of neoadjuvant chemoradiotherapy plus surgery for esophageal cancer: The randomized controlled CROSS trial. J Clin Oncol, 2021, 39(18): 1995-2004.
9. Leng X, He W, Yang H, et al. Prognostic impact of postoperative lymph node metastases after neoadjuvant chemoradiotherapy for locally advanced squamous cell carcinoma of esophagus: From the results of NEOCRTEC5010, a randomized multicenter study. Ann Surg, 2021, 274(6): e1022-e1029.
10. Moujaess E, Haddad FG, Eid R, et al. The emerging use of immune checkpoint blockade in the adjuvant setting for solid tumors: A review. Immunotherapy, 2019, 11(16): 1409-1422.
11. 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.
12. 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.
13. 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.
14. Park SY, Hong MH, Kim HR, et al. The feasibility and safety of radical esophagectomy in patients receiving neoadjuvant chemoradiotherapy with pembrolizumab for esophageal squamous cell carcinoma. J Thorac Dis, 2020, 12(11): 6426-6434.
15. Shang X, Zhao G, Liang F, et al. Safety and effectiveness of pembrolizumab combined with paclitaxel and cisplatin as neoadjuvant therapy followed by surgery for locally advanced resectable (stage Ⅲ) esophageal squamous cell carcinoma: A study protocol for a prospective, single-arm, single-center, open-label, phase-Ⅱ trial (Keystone-001). Ann Transl Med, 2022, 10(4): 229.
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. 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.
18. Samson P, Robinson C, Bradley J, et al. Neoadjuvant chemotherapy versus chemoradiation prior to esophagectomy: Impact on rate of complete pathologic response and survival in esophageal cancer patients. J Thorac Oncol, 2016, 11(12): 2227-2237.
19. Klevebro F, Alexandersson von Döbeln G, Wang N, et al. A randomized clinical trial of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the oesophagus or gastro-oesophageal junction. Ann Oncol, 2016, 27(4): 660-667.
20. 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.
21. 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.
22. 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.
23. Lv H, Tian Y, Li J, et al. Neoadjuvant sintilimab plus chemotherapy in resectable locally advanced esophageal squamous cell carcinoma. Front Oncol, 2022 Apr 29: 12: 864533.
24. Liu J, Li J, Lin W, et al. Neoadjuvant camrelizumab plus chemotherapy for resectable, locally advanced esophageal squamous cell carcinoma (NIC-ESCC2019): A multicenter, phase 2 study. Int J Cancer, 2022, 151(1): 128-137.
25. Yang W, Xing X, Yeung SJ, et al. Neoadjuvant programmed cell death 1 blockade combined with chemotherapy for resectable esophageal squamous cell carcinoma. J Immunother Cancer, 2022, 10(1): e003497.
26. Xing W, Zhao L, Zheng Y, et al. The sequence of chemotherapy and toripalimab might influence the efficacy of neoadjuvant chemoimmunotherapy in locally advanced esophageal squamous cell cancer—A phase Ⅱ study. Front Immunol, 2021, 12: 772450.
27. Wu Z, Zheng Q, Chen H, et al. Efficacy and safety of neoadjuvant chemotherapy and immunotherapy in locally resectable advanced esophageal squamous cell carcinoma. J Thorac Dis, 2021, 13(6): 3518-3528.
28. He W, Leng X, Mao T, et al. Toripalimab plus paclitaxel and carboplatin as neoadjuvant therapy in locally advanced resectable esophageal squamous cell carcinoma. Oncologist, 2022, 27(1): e18-e28.18-28.
29. 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.
30. Sihag S, Ku GY, Tan KS, et al. Safety and feasibility of esophagectomy following combined immunotherapy and chemoradiotherapy for esophageal cancer. J Thorac Cardiovasc Surg, 2021, 161(3): 836-843.
31. 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: 232-241.144-232.
32. van den Ende T, de Clercq NC, van Berge Henegouwen MI, et al. Neoadjuvant chemoradiotherapy combined with atezolizumab for resectable esophageal adenocarcinoma: A single-arm phase Ⅱ feasibility trial (PERFECT). Clin Cancer Res, 2021, 27(12): 3351-3359.
33. Yang G, Su X, Huang Y, et al. Intensive cycles of neoadjuvant camrelizumab combined with chemotherapy in locally advanced esophageal squamous cell carcinoma: A single-arm, phase Ⅱtrial. J Transl Med, 2023, 21(1): 411.
34. Blakely CM, McCoach CE. Role of MPR as an early signal for efficacy in neoadjuvant studies. Clin Cancer Res, 2020, 26(14): 3499-3500.
35. Yang Y, Liu J, Liu Z, et al. Two-year outcomes of clinical N2-3 esophageal squamous cell carcinoma after neoadjuvant chemotherapy and immunotherapy from the phase 2 NICE study. J Thorac Cardiovasc Surg, 2024, 167(3): 838-847.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Latest ArticlesAnalysis of short-term efficacy and safety of neoadjuvant sintilimab plus chemotherapy for locally advanced resectable esophageal squamous cell carcinoma

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