Prognostic impact of adjuvant therapy on patients with esophageal squamous cell carcinoma receiving neoadjuvant therapy plus esophagectomy: A systematic review and meta-analysis_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

HU Zihao ¹ , SONG Peidong ¹ , CHEN Donglai ² , XU Sukai ¹ , TAN Lijie ² ,  SANG Yonghua ¹ , CHEN Yongbing ¹

1. Department of Thoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, Jiangsu, P. R. China;
2. Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China;

Corresponding author：

SANG Yonghua, Email: sangyh1983@sina.com

Keywords：

Esophageal squamous cell carcinoma; neoadjuvant therapy; adjuvant therapy; systematic review/meta-analysis

DOI：

10.7507/1007-4848.202212069

Video：

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Objective To investigate whether adjuvant therapy can bring survival benefits to patients with esophageal squamous cell carcinoma (ESCC) who have received neoadjuvant therapy plus esophagectomy. Methods Studies were identified by searching databases including PubMed, EMbase, Web of Science, The Cochrane Library and CNKI from inception to November 2022 to collect studies which conformed to the objective of this study. Clinical outcomes including overall survival (OS) and recurrence-free survival (RFS) were extracted from eligible studies after screening. RevMan 5.4 and Stata 14.0 were used to perform the meta-analysis. Results A total of 9 studies were selected including 1 340 patients. Compared with the neoadjuvant therapy plus surgery (NS) group, the neoadjuvant therapy plus surgery+adjuvant therapy (NS+A) group had no significant benefit in the OS [HR=0.88, 95%CI (0.75, 1.02), P=0.09], but had remarkable benefit in the RFS [HR=0.75, 95%CI (0.58, 0.97), P=0.03]. Subgroup analysis by nodal status showed that adjuvant therapy could improve the RFS of patients with node-positive disease. Prolonged OS was observed in the patients with both positive and negative nodes but not in the patients with only positive nodes. In terms of the subgroup analysis by prescription, it revealed that triple agents exhibited advantages in improving RFS but not OS. However, dual agents did not bring additional survival benefits to the NS+A group compared with the NS group. Subgroup analysis by adjuvant therapy indicated that neither postoperative chemoradiotherapy nor chemotherapy improved OS, whereas postoperative chemoradiation elongated RFS. Conclusion Adjuvant therapy can improve the prognosis of patients with ESCC after neoadjuvant therapy followed by esophagectomy.

Citation： HU Zihao, SONG Peidong, CHEN Donglai, XU Sukai, TAN Lijie, SANG Yonghua, CHEN Yongbing. Prognostic impact of adjuvant therapy on patients with esophageal squamous cell carcinoma receiving neoadjuvant therapy plus esophagectomy: A systematic review and meta-analysis. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2024, 31(10): 1505-1513. doi: 10.7507/1007-4848.202212069 Copy

1.	Ajani JA, D'Amico TA, Bentrem DJ, et al. Esophageal and esophagogastric junction cancers, version 2. 2023, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw, 2023, 21(4): 393-422.
2.	Fitzmaurice C, Akinyemiju TF, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2016: A systematic analysis for the global burden of disease study. JAMA Oncol, 2018, 4(11): 1553-1568.
3.	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.
4.	Liang H, Fan JH, Qiao YL. Epidemiology, etiology, and prevention of esophageal squamous cell carcinoma in China. Cancer Biol Med, 2017, 14(1): 33-41.
5.	Yuan MW, Wang HH, Duan RF, et al. Analysis on cancer incidence and mortality attributed to human papillomavirus infection in China, 2016. Zhonghua Liu Xing Bing Xue Za Zhi, 2022, 43(5): 702-708.
6.	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.
7.	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.
8.	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.
9.	陆寓非, 孙亚楠, 郑晓丽, 等. 食管鳞癌新辅助放化疗术后化疗疗效分析. 中华肿瘤防治杂志, 2015, 22(6): 457-462.Lu YF, Sun YN, Zheng XL, et al. Clinical efficacy of postoperative chemotherapy for esophageal squamous cell cancer after preoperative chemoradiotherapy combined with surgery. Chin J Cancer Prev Treat, 2015, 22(6): 457-462.
10.	Zhao Y, Dai Z, Min W, et al. Perioperative versus preoperative chemotherapy with surgery in patients with resectable squamous cell carcinoma of esophagus: A phase Ⅲrandomized trial. J Thorac Oncol, 2015, 10(9): 1349-1356.
11.	Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med, 2021, 384(13): 1191-1203.
12.	Hsu HY, Chao YK, Hsieh CH, et al. Postoperative adjuvant therapy improves survival in pathologic nonresponders after neoadjuvant chemoradiation for esophageal squamous cell carcinoma: A propensity-matched analysis. Ann Thorac Surg, 2016, 102(5): 1687-1693.
13.	Yan W, Zhao P, Fu H, et al. Survival after induction chemotherapy and esophagectomy is not improved by adjuvant chemotherapy. Ann Thorac Surg, 2019, 108(5): 1505-1513.
14.	Huang Z, Li S, Yang X, et al. Long-term survival of patients with locally advanced esophageal squamous cell carcinoma receiving esophagectomy following neoadjuvant chemotherapy: A cohort study. Cancer Manag Res, 2019, 11: 1299-1308.
15.	Matsuura N, Yamasaki M, Yamashita K, et al. The role of adjuvant chemotherapy in esophageal cancer patients after neoadjuvant chemotherapy plus surgery. Esophagus, 2021, 18(3): 559-565.
16.	Imai T, Tanaka Y, Sato Y, et al. The role of adjuvant chemotherapy for esophageal squamous cell carcinoma patients with pathological positive lymph nodes after neoadjuvant chemotherapy followed by esophagectomy: A single institute retrospective analysis. Indian J Surg Oncol, 2021, 12(4): 776-784.
17.	Park S, Sun JM, Choi YL, et al. Adjuvant durvalumab for esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy: A placebo-controlled, randomized, double-blind, phaseⅡstudy. ESMO Open, 2022, 7(1): 100385.
18.	Burmeister BH, Smithers BM, Gebski V, et al. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: A randomised controlled phaseⅢtrial. Lancet Oncol, 2005, 6(9): 659-668.
19.	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.
20.	Mariette C, Dahan L, Mornex F, et al. Surgery alone versus chemoradiotherapy followed by surgery for stageⅠ andⅡesophageal cancer: Final analysis of randomized controlled phaseⅢ trial FFCD 9901. J Clin Oncol, 2014, 32(23): 2416-2422.
21.	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.
22.	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.
23.	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.
24.	Kidane B, Coughlin S, Vogt K, et al. Preoperative chemotherapy for resectable thoracic esophageal cancer. Cochrane Database Syst Rev, 2015, 2015(5): CD001556.
25.	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.
26.	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.
27.	中国临床肿瘤学会 (CSCO). 食管癌诊疗指南 (2022). 北京: 中国临床肿瘤学会, 2022.Chinese Society of Clinical Oncology. Standardization for diagnosis and treatment of esophageal cancer (2022 edition). Beijing: Chinese Society of Clinical Oncology, 2022.
28.	Semenkovich TR, Subramanian M, Yan Y, et al. Adjuvant therapy for node-positive esophageal cancer after induction and surgery: A multisite study. Ann Thorac Surg, 2019, 108(3): 828-836.
29.	Drake J, Tauer K, Portnoy D, et al. Adjuvant chemotherapy is associated with improved survival in patients with nodal metastases after neoadjuvant therapy and esophagectomy. J Thorac Dis, 2019, 11(6): 2546-2554.
30.	Samson P, Puri V, Lockhart AC, et al. Adjuvant chemotherapy for patients with pathologic node-positive esophageal cancer after induction chemotherapy is associated with improved survival. J Thorac Cardiovasc Surg, 2018, 156(4): 1725-1735.
31.	Mokdad AA, Yopp AC, Polanco PM, et al. Adjuvant chemotherapy vs. postoperative observation following preoperative chemoradiotherapy and resection in gastroesophageal cancer: A propensity score-matched analysis. JAMA Oncol, 2018, 4(1): 31-38.
32.	Hoeppner J, Zirlik K, Brunner T, et al. Multimodal treatment of locally advanced esophageal adenocarcinoma: Which regimen should we choose? Outcome analysis of perioperative chemotherapy versus neoadjuvant chemoradiation in 105 patients. J Surg Oncol, 2014, 109(3): 287-293.
33.	Yang Y, Zhou X, Tang L, et al. Role of perioperative chemotherapy in lymph node-negative esophageal cancer after resection: A population-based study with propensity score-matched analysis. Am J Clin Oncol, 2019, 42(12): 924-931.
34.	Ando N, Iizuka T, Ide H, et al. Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: A Japan Clinical Oncology Group Study―JCOG9204. J Clin Oncol, 2003, 21(24): 4592-4596.
35.	Zhang J, Chen HQ, Zhang YW, et al. Adjuvant chemotherapy in oesophageal cancer: A meta-analysis and experience from the Shanghai Cancer Hospital. J Int Med Res, 2008, 36(5): 875-882.
36.	Raja S, Rice TW, Lu M, et al. Adjuvant therapy after neoadjuvant therapy for esophageal cancer: Who needs it? Ann Surg, 2023, 278(2): e240-e249.
37.	Shang X, Zhang W, Zhao G, et al. Pembrolizumab combined with neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy followed by surgery for locally advanced oesophageal squamous cell carcinoma: Protocol for a multicentre, prospective, randomized-controlled, phase Ⅲ clinical study (Keystone-002). Front Oncol, 2022, 12: 831345.

1. Ajani JA, D'Amico TA, Bentrem DJ, et al. Esophageal and esophagogastric junction cancers, version 2. 2023, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw, 2023, 21(4): 393-422.
2. Fitzmaurice C, Akinyemiju TF, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2016: A systematic analysis for the global burden of disease study. JAMA Oncol, 2018, 4(11): 1553-1568.
3. 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.
4. Liang H, Fan JH, Qiao YL. Epidemiology, etiology, and prevention of esophageal squamous cell carcinoma in China. Cancer Biol Med, 2017, 14(1): 33-41.
5. Yuan MW, Wang HH, Duan RF, et al. Analysis on cancer incidence and mortality attributed to human papillomavirus infection in China, 2016. Zhonghua Liu Xing Bing Xue Za Zhi, 2022, 43(5): 702-708.
6. 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.
7. 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.
8. 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.
9. 陆寓非, 孙亚楠, 郑晓丽, 等. 食管鳞癌新辅助放化疗术后化疗疗效分析. 中华肿瘤防治杂志, 2015, 22(6): 457-462.Lu YF, Sun YN, Zheng XL, et al. Clinical efficacy of postoperative chemotherapy for esophageal squamous cell cancer after preoperative chemoradiotherapy combined with surgery. Chin J Cancer Prev Treat, 2015, 22(6): 457-462.
10. Zhao Y, Dai Z, Min W, et al. Perioperative versus preoperative chemotherapy with surgery in patients with resectable squamous cell carcinoma of esophagus: A phase Ⅲrandomized trial. J Thorac Oncol, 2015, 10(9): 1349-1356.
11. Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med, 2021, 384(13): 1191-1203.
12. Hsu HY, Chao YK, Hsieh CH, et al. Postoperative adjuvant therapy improves survival in pathologic nonresponders after neoadjuvant chemoradiation for esophageal squamous cell carcinoma: A propensity-matched analysis. Ann Thorac Surg, 2016, 102(5): 1687-1693.
13. Yan W, Zhao P, Fu H, et al. Survival after induction chemotherapy and esophagectomy is not improved by adjuvant chemotherapy. Ann Thorac Surg, 2019, 108(5): 1505-1513.
14. Huang Z, Li S, Yang X, et al. Long-term survival of patients with locally advanced esophageal squamous cell carcinoma receiving esophagectomy following neoadjuvant chemotherapy: A cohort study. Cancer Manag Res, 2019, 11: 1299-1308.
15. Matsuura N, Yamasaki M, Yamashita K, et al. The role of adjuvant chemotherapy in esophageal cancer patients after neoadjuvant chemotherapy plus surgery. Esophagus, 2021, 18(3): 559-565.
16. Imai T, Tanaka Y, Sato Y, et al. The role of adjuvant chemotherapy for esophageal squamous cell carcinoma patients with pathological positive lymph nodes after neoadjuvant chemotherapy followed by esophagectomy: A single institute retrospective analysis. Indian J Surg Oncol, 2021, 12(4): 776-784.
17. Park S, Sun JM, Choi YL, et al. Adjuvant durvalumab for esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy: A placebo-controlled, randomized, double-blind, phaseⅡstudy. ESMO Open, 2022, 7(1): 100385.
18. Burmeister BH, Smithers BM, Gebski V, et al. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: A randomised controlled phaseⅢtrial. Lancet Oncol, 2005, 6(9): 659-668.
19. 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.
20. Mariette C, Dahan L, Mornex F, et al. Surgery alone versus chemoradiotherapy followed by surgery for stageⅠ andⅡesophageal cancer: Final analysis of randomized controlled phaseⅢ trial FFCD 9901. J Clin Oncol, 2014, 32(23): 2416-2422.
21. 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.
22. 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.
23. 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.
24. Kidane B, Coughlin S, Vogt K, et al. Preoperative chemotherapy for resectable thoracic esophageal cancer. Cochrane Database Syst Rev, 2015, 2015(5): CD001556.
25. 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.
26. 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.
27. 中国临床肿瘤学会 (CSCO). 食管癌诊疗指南 (2022). 北京: 中国临床肿瘤学会, 2022.Chinese Society of Clinical Oncology. Standardization for diagnosis and treatment of esophageal cancer (2022 edition). Beijing: Chinese Society of Clinical Oncology, 2022.
28. Semenkovich TR, Subramanian M, Yan Y, et al. Adjuvant therapy for node-positive esophageal cancer after induction and surgery: A multisite study. Ann Thorac Surg, 2019, 108(3): 828-836.
29. Drake J, Tauer K, Portnoy D, et al. Adjuvant chemotherapy is associated with improved survival in patients with nodal metastases after neoadjuvant therapy and esophagectomy. J Thorac Dis, 2019, 11(6): 2546-2554.
30. Samson P, Puri V, Lockhart AC, et al. Adjuvant chemotherapy for patients with pathologic node-positive esophageal cancer after induction chemotherapy is associated with improved survival. J Thorac Cardiovasc Surg, 2018, 156(4): 1725-1735.
31. Mokdad AA, Yopp AC, Polanco PM, et al. Adjuvant chemotherapy vs. postoperative observation following preoperative chemoradiotherapy and resection in gastroesophageal cancer: A propensity score-matched analysis. JAMA Oncol, 2018, 4(1): 31-38.
32. Hoeppner J, Zirlik K, Brunner T, et al. Multimodal treatment of locally advanced esophageal adenocarcinoma: Which regimen should we choose? Outcome analysis of perioperative chemotherapy versus neoadjuvant chemoradiation in 105 patients. J Surg Oncol, 2014, 109(3): 287-293.
33. Yang Y, Zhou X, Tang L, et al. Role of perioperative chemotherapy in lymph node-negative esophageal cancer after resection: A population-based study with propensity score-matched analysis. Am J Clin Oncol, 2019, 42(12): 924-931.
34. Ando N, Iizuka T, Ide H, et al. Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: A Japan Clinical Oncology Group Study―JCOG9204. J Clin Oncol, 2003, 21(24): 4592-4596.
35. Zhang J, Chen HQ, Zhang YW, et al. Adjuvant chemotherapy in oesophageal cancer: A meta-analysis and experience from the Shanghai Cancer Hospital. J Int Med Res, 2008, 36(5): 875-882.
36. Raja S, Rice TW, Lu M, et al. Adjuvant therapy after neoadjuvant therapy for esophageal cancer: Who needs it? Ann Surg, 2023, 278(2): e240-e249.
37. Shang X, Zhang W, Zhao G, et al. Pembrolizumab combined with neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy followed by surgery for locally advanced oesophageal squamous cell carcinoma: Protocol for a multicentre, prospective, randomized-controlled, phase Ⅲ clinical study (Keystone-002). Front Oncol, 2022, 12: 831345.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Prognostic impact of adjuvant therapy on patients with esophageal squamous cell carcinoma receiving neoadjuvant therapy plus esophagectomy: A systematic review and meta-analysis

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