The efficacy of neoadjuvant therapy for esophageal cancer: A network meta-analysis_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

GAO Xin ^1,2 , WANG Shuolian ² , XU Shuai ³ , MA Wenwen ¹ , XU Ziang ¹ , HU Gawei ¹ ,  LI Qingxin ¹

1. The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, 730050, Lanzhou, P. R. China;
2. Graduate School of Ningxia Medical University, Yinchuan, 750004, P. R. China;
3. Graduate School of Hebei North University, Zhangjiakou, 075000, Hebei, P. R. China;

Corresponding author：

LI Qingxin, Email: liqxchest@163.com

Keywords：

Esophageal cancer; neoadjuvant therapy; chemotherapy; radiotherapy; chemoradiotherapy; network meta-analysis

DOI：

10.7507/1007-4848.202211041

Video：

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Objective To explore the best neoadjuvant treatment strategy for esophageal cancer and provide a theoretical basis for clinical formulation of neoadjuvant treatment plan. Methods PubMed, EMbase, The Cochrane Library, Web of Science, CNKI, Wanfang, and VIP were searched from inception to May 2022. Two researchers independently performed literature screening and data extraction. The quality of the studies was evaluated by the Cochrane risk of bias tool, and data analysis was performed in RStudio environment using R3.6.3 software. Results A total of 24 studies were included, covering 5 286 patients treated with surgery alone, neoadjuvant chemotherapy (NCT), neoadjuvant radiotherapy (NRT), or neoadjuvant chemoradiotherapy (NCRT) followed by combined surgical treatment. The risk of bias of the studies was low. The results of the network meta-analysis showed that combined surgical treatments after NCRT [HR=0.77, 95%CI (0.70, 0.85)] and NCT [HR=0.89, 95%CI (0.81, 0.98)] were effective methods to improve patients' overall survival (OS) compared with surgery alone. In addition, NCRT could significantly reduce the incidence of local recurrence [OR=0.43, 95%CI (0.30, 0.58)] and distant metastasis [OR=0.71, 95%CI (0.52, 0.93)] in patients with esophageal cancer. However, NCRT [RR=1.30, 95%CI (0.77, 2.20)] increased the mortality rate of patients at 30 d after surgery. Conclusion The available evidence suggests that NCRT combined with surgery is the best option for treating patients with resectable esophageal cancer, but this treatment carries the risk of increased 30 d postoperative mortality. Future studies should focus on optimizing the NCRT regimen with the aim of improving patients’ OS while effectively reducing postoperative mortality. In addition, more high-quality randomized controlled trials are needed to support the results of the study.

Citation： GAO Xin, WANG Shuolian, XU Shuai, MA Wenwen, XU Ziang, HU Gawei, LI Qingxin. The efficacy of neoadjuvant therapy for esophageal cancer: A network meta-analysis. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2024, 31(7): 1035-1042. doi: 10.7507/1007-4848.202211041 Copy

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.	Nobel TB, Livschitz J, Xing XX, et al. Surveillance implications of recurrence patterns in early node-negative esophageal adenocarcinoma. Ann Thorac Surg, 2019, 108(6): 1640-1647.
3.	谭黎杰, 黄志良. 食管癌新辅助免疫治疗的现状及未来. 中华消化外科杂志, 2021, 20(6): 635-638.
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. 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.
6.	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):1-11.
7.	Mariette C, Dahan L, Mornex F, et al. Surgery alone versus chemoradiotherapy followed by surgery for stageⅠandⅡesophageal cancer: Final analysis of randomized controlled phase Ⅲ trial FFCD 9901. J Clin Oncol, 2014, 32(23): 2416-2422.
8.	Ajani JA, D'Amico TA, Bentrem DJ, et al. Esophageal and esophagogastric junction cancers, version 2. 2019, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw, 2019, 17(7): 855-883.
9.	Liu N, Zhou Y, Lee JJ. IPDfromKM: Reconstruct individual patient data from published Kaplan-Meier survival curves. BMC Med Res Methodol, 2021, 21(1): 111.
10.	Shim S, Yoon BH, Shin IS, et al. Network meta-analysis: Application and practice using Stata. Epidemiol Health, 2017, 39: e2017047.
11.	Gignoux M, Roussel A, Paillot B, et al. The value of preoperative radiotherapy in esophageal cancer: Results of a study of the E. O. R. T. C. World J Surg, 1987, 11(4): 426-432.
12.	Nygaard K, Hagen S, Hansen HS, et al. Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma: A randomized, multicenter study of pre-operative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer. World J Surg, 1992, 16(6): 1104-1109.
13.	Walsh TN, Noonan N, Hollywood D, et al. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med, 1996, 335(7): 462-467.
14.	Bosset JF, Gignoux M, Triboulet JP, et al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med, 1997, 337(3): 161-167.
15.	Law S, Fok M, Chow S, et al. Preoperative chemotherapy versus surgical therapy alone for squamous cell carcinoma of the esophagus: A prospective randomized trial. J Thorac Cardiovasc Surg, 1997, 114(2): 210-217.
16.	Ancona E, Ruol A, Santi S, et al. Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma: Final report of a randomized, controlled trial of preoperative chemotherapy versus surgery alone. Cancer, 2001, 91(11): 2165-2174.
17.	Urba SG, Orringer MB, Turrisi A, et al. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol, 2001, 19(2): 305-313.
18.	安丰山, 黄金球, 谢映涛, 等. 食管癌新辅助放化疗的前瞻性临床研究. 中华肿瘤杂志, 2003, 25(4): 376-379.
19.	Burmeister BH, Smithers BM, Gebski V, et al. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: A randomised controlled phaseⅢ trial. Lancet Oncol, 2005, 6(9): 659-668.
20.	Kelsen DP, Winter KA, Gunderson LL, et al. Long-term results of RTOG trial 8911 (USA Intergroup 113): A random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer. J Clin Oncol, 2007, 25(24): 3719-3725.
21.	Tepper J, Krasna MJ, Niedzwiecki D, et al. Phase Ⅲ trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol, 2008, 26(7): 1086-1092.
22.	Allum WH, Stenning SP, Bancewicz J, et al. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol, 2009, 27(30): 5062-5067.
23.	Burmeister BH, Thomas JM, Burmeister EA, et al. Is concurrent radiation therapy required in patients receiving preoperative chemotherapy for adenocarcinoma of the oesophagus? A randomised phaseⅡ trial. Eur J Cancer, 2011, 47(3): 354-360.
24.	Boonstra JJ, Kok TC, Wijnhoven BP, et al. Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: Long-term results of a randomized controlled trial. BMC Cancer, 2011, 11: 181.
25.	李孝鹏, 丁宁, 白光平, 等. 新辅助放化疗联合手术与单纯手术治疗局部晚期食管癌的疗效比较. 肿瘤防治研究, 2014, 41(5): 464-467.
26.	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.
27.	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.
28.	Cao XF, He XT, Ji L, et al. Effects of neoadjuvant radiochemotherapy on pathological staging and prognosis for locally advanced esophageal squamous cell carcinoma. Dis Esophagus, 2009, 22(6): 477-481.
29.	Lv J, Cao XF, Zhu B, et al. Long-term efficacy of perioperative chemoradiotherapy on esophageal squamous cell carcinoma. World J Gastroenterol, 2010, 16(13): 1649-1654.
30.	周凯, 王伟, 相加庆. 新辅助化放疗联合手术治疗局部晚期食管癌30例. 中国临床研究, 2018, 31(10): 1375-1378.
31.	Wang DB, Zhang X, Han HL, et al. Neoadjuvant chemoradiotherapy could improve survival outcomes for esophageal carcinoma: A meta-analysis. Dig Dis Sci, 2012, 57(12): 3226-3233.
32.	杨振宇, 朱泽武, 阿来古哈, 等. 新辅助放化疗结合手术与单纯手术治疗可切除食管癌的系统评价与Meta分析. 中国胸心血管外科临床杂志, 2017, 24(11): 867-879.
33.	van der Wilk BJ, Eyck BM, Lagarde SM, et al. The optimal neoadjuvant treatment of locally advanced esophageal cancer. J Thorac Dis, 2019, 11(Suppl 5): S621-S631.
34.	Sato Y, Motoyama S, Wada Y, et al. Neoadjuvant chemoradiotherapy followed by esophagectomy with three-field lymph node dissection for thoracic esophageal squamous cell carcinoma patients with clinical stage Ⅲ and with supraclavicular lymph node metastasis. Cancers (Basel), 2021, 13(5): 983.
35.	Liang M, Liu Y, Zhang Z, et al. Fusobacterium nucleatum induces MDSCs enrichment via activation the NLRP3 inflammosome in ESCC cells, leading to cisplatin resistance. Ann Med, 2022, 54(1): 989-1003.
36.	Tan JT, Yang Y, Mao NQ, et al. Effect of neoadjuvant chemoradiotherapy on perioperative immune function of patients with locally advanced esophageal cancer. Dis Esophagus, 2017, 30(2): 1-8.
37.	Sjoquist KM, Burmeister BH, Smithers BM, et al. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: An updated meta-analysis. Lancet Oncol, 2011, 12(7): 681-692.
38.	陈良亮, 陆晶, 饶钰君, 等. 内镜和外科手术治疗T1N0期食管肿瘤安全性和有效性的系统评价与Meta分析. 中国胸心血管外科临床杂志, 2022, 29(2): 158-165.
39.	Ge F, Huo Z, Cai X, et al. Evaluation of clinical and safety outcomes of neoadjuvant immunotherapy combined with chemotherapy for patients with resectable esophageal cancer: A systematic review and meta-analysis. JAMA Netw Open, 2022, 5(11): e2239778.
40.	Wang Z, Shao C, Wang Y, et al. Efficacy and safety of neoadjuvant immunotherapy in surgically resectable esophageal cancer: A systematic review and meta-analysis. Int J Surg, 2022, 104: 106767.

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. Nobel TB, Livschitz J, Xing XX, et al. Surveillance implications of recurrence patterns in early node-negative esophageal adenocarcinoma. Ann Thorac Surg, 2019, 108(6): 1640-1647.
3. 谭黎杰, 黄志良. 食管癌新辅助免疫治疗的现状及未来. 中华消化外科杂志, 2021, 20(6): 635-638.
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. 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.
6. 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):1-11.
7. Mariette C, Dahan L, Mornex F, et al. Surgery alone versus chemoradiotherapy followed by surgery for stageⅠandⅡesophageal cancer: Final analysis of randomized controlled phase Ⅲ trial FFCD 9901. J Clin Oncol, 2014, 32(23): 2416-2422.
8. Ajani JA, D'Amico TA, Bentrem DJ, et al. Esophageal and esophagogastric junction cancers, version 2. 2019, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw, 2019, 17(7): 855-883.
9. Liu N, Zhou Y, Lee JJ. IPDfromKM: Reconstruct individual patient data from published Kaplan-Meier survival curves. BMC Med Res Methodol, 2021, 21(1): 111.
10. Shim S, Yoon BH, Shin IS, et al. Network meta-analysis: Application and practice using Stata. Epidemiol Health, 2017, 39: e2017047.
11. Gignoux M, Roussel A, Paillot B, et al. The value of preoperative radiotherapy in esophageal cancer: Results of a study of the E. O. R. T. C. World J Surg, 1987, 11(4): 426-432.
12. Nygaard K, Hagen S, Hansen HS, et al. Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma: A randomized, multicenter study of pre-operative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer. World J Surg, 1992, 16(6): 1104-1109.
13. Walsh TN, Noonan N, Hollywood D, et al. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med, 1996, 335(7): 462-467.
14. Bosset JF, Gignoux M, Triboulet JP, et al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med, 1997, 337(3): 161-167.
15. Law S, Fok M, Chow S, et al. Preoperative chemotherapy versus surgical therapy alone for squamous cell carcinoma of the esophagus: A prospective randomized trial. J Thorac Cardiovasc Surg, 1997, 114(2): 210-217.
16. Ancona E, Ruol A, Santi S, et al. Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma: Final report of a randomized, controlled trial of preoperative chemotherapy versus surgery alone. Cancer, 2001, 91(11): 2165-2174.
17. Urba SG, Orringer MB, Turrisi A, et al. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol, 2001, 19(2): 305-313.
18. 安丰山, 黄金球, 谢映涛, 等. 食管癌新辅助放化疗的前瞻性临床研究. 中华肿瘤杂志, 2003, 25(4): 376-379.
19. Burmeister BH, Smithers BM, Gebski V, et al. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: A randomised controlled phaseⅢ trial. Lancet Oncol, 2005, 6(9): 659-668.
20. Kelsen DP, Winter KA, Gunderson LL, et al. Long-term results of RTOG trial 8911 (USA Intergroup 113): A random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer. J Clin Oncol, 2007, 25(24): 3719-3725.
21. Tepper J, Krasna MJ, Niedzwiecki D, et al. Phase Ⅲ trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol, 2008, 26(7): 1086-1092.
22. Allum WH, Stenning SP, Bancewicz J, et al. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol, 2009, 27(30): 5062-5067.
23. Burmeister BH, Thomas JM, Burmeister EA, et al. Is concurrent radiation therapy required in patients receiving preoperative chemotherapy for adenocarcinoma of the oesophagus? A randomised phaseⅡ trial. Eur J Cancer, 2011, 47(3): 354-360.
24. Boonstra JJ, Kok TC, Wijnhoven BP, et al. Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: Long-term results of a randomized controlled trial. BMC Cancer, 2011, 11: 181.
25. 李孝鹏, 丁宁, 白光平, 等. 新辅助放化疗联合手术与单纯手术治疗局部晚期食管癌的疗效比较. 肿瘤防治研究, 2014, 41(5): 464-467.
26. 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.
27. 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.
28. Cao XF, He XT, Ji L, et al. Effects of neoadjuvant radiochemotherapy on pathological staging and prognosis for locally advanced esophageal squamous cell carcinoma. Dis Esophagus, 2009, 22(6): 477-481.
29. Lv J, Cao XF, Zhu B, et al. Long-term efficacy of perioperative chemoradiotherapy on esophageal squamous cell carcinoma. World J Gastroenterol, 2010, 16(13): 1649-1654.
30. 周凯, 王伟, 相加庆. 新辅助化放疗联合手术治疗局部晚期食管癌30例. 中国临床研究, 2018, 31(10): 1375-1378.
31. Wang DB, Zhang X, Han HL, et al. Neoadjuvant chemoradiotherapy could improve survival outcomes for esophageal carcinoma: A meta-analysis. Dig Dis Sci, 2012, 57(12): 3226-3233.
32. 杨振宇, 朱泽武, 阿来古哈, 等. 新辅助放化疗结合手术与单纯手术治疗可切除食管癌的系统评价与Meta分析. 中国胸心血管外科临床杂志, 2017, 24(11): 867-879.
33. van der Wilk BJ, Eyck BM, Lagarde SM, et al. The optimal neoadjuvant treatment of locally advanced esophageal cancer. J Thorac Dis, 2019, 11(Suppl 5): S621-S631.
34. Sato Y, Motoyama S, Wada Y, et al. Neoadjuvant chemoradiotherapy followed by esophagectomy with three-field lymph node dissection for thoracic esophageal squamous cell carcinoma patients with clinical stage Ⅲ and with supraclavicular lymph node metastasis. Cancers (Basel), 2021, 13(5): 983.
35. Liang M, Liu Y, Zhang Z, et al. Fusobacterium nucleatum induces MDSCs enrichment via activation the NLRP3 inflammosome in ESCC cells, leading to cisplatin resistance. Ann Med, 2022, 54(1): 989-1003.
36. Tan JT, Yang Y, Mao NQ, et al. Effect of neoadjuvant chemoradiotherapy on perioperative immune function of patients with locally advanced esophageal cancer. Dis Esophagus, 2017, 30(2): 1-8.
37. Sjoquist KM, Burmeister BH, Smithers BM, et al. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: An updated meta-analysis. Lancet Oncol, 2011, 12(7): 681-692.
38. 陈良亮, 陆晶, 饶钰君, 等. 内镜和外科手术治疗T1N0期食管肿瘤安全性和有效性的系统评价与Meta分析. 中国胸心血管外科临床杂志, 2022, 29(2): 158-165.
39. Ge F, Huo Z, Cai X, et al. Evaluation of clinical and safety outcomes of neoadjuvant immunotherapy combined with chemotherapy for patients with resectable esophageal cancer: A systematic review and meta-analysis. JAMA Netw Open, 2022, 5(11): e2239778.
40. Wang Z, Shao C, Wang Y, et al. Efficacy and safety of neoadjuvant immunotherapy in surgically resectable esophageal cancer: A systematic review and meta-analysis. Int J Surg, 2022, 104: 106767.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

The efficacy of neoadjuvant therapy for esophageal cancer: A network meta-analysis

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