Timing of surgery for esophageal cancer patients after neoadjuvant chemoradiotherapy: A systematic review and meta-analysis_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

HE Feng ¹ , TIE Hongtao ² , LANG Weisi ¹ , LUO Jun ² , CHEN Dan ² , WU Qingchen ² ,  YANG Long ¹

1. Department of Cardiothoracic Surgery, The Fifth People’s Hospital of Chongqing, Chongqing, 400062, P.R.China;
2. Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P.R.China;

Corresponding author：

YANG Long, Email: 13908326319@163.com

Keywords：

Esophageal neoplasms; neoadjuvant chemoradiotherapy; resection; interval; systematic review and meta-analysis

DOI：

10.7507/1007-4848.201812066

Video：

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Objective To investigate the effect of the interval between neoadjuvant chemoradiotherapy (nCRT) and surgery on the clinical outcome of esophageal cancer.Methods PubMed and EMbase databases from inception to March 2018 were retrieved by computer. A random-effect model was used for all meta-analyses irrespective of heterogeneity. The meta-analysis was performed by RevMan5.3 software. The primary outcomes were operative mortality, incidence of anastomotic leakage, and overall survival; secondary outcomes were pathologic complete remission rate, R0 resection rate, and positive resection margin rate.Results A total of 17 studies with 18 173 patients were included. Among them, 13 were original studies with 2 950 patients, and 4 were database-based studies with a total of 15 223 patients. The results showed a significant positive correlation between the interval and operative mortality (Spearman coefficient=0.360, P=0.027). Dose-response meta-analysis revealed that there was a relatively better time window for surgery after nCRT. Further analysis for primary outcomes at different time cut-offs found the following results: (1) when the time cut-off point within 30-70 days, the shorter interval was associated with a reduced operative mortality (7-8 weeks: RR=0.67, 95% CI 0.55-0.81, P<0.05; 30-46 days: RR=0.63, 95%CI 0.47-0.85, P<0.05; 60-70 days: RR=0.64, 95%CI 0.48-0.85, P<0.05); (2) when the time cut-off point within 30-46 days, the shorter interval correlated with a reduced incidence of anastomotic leakage (RR=0.39, 95%CI 0.21-0.72, P<0.05); when the time cut-off point within 7-8 weeks, the shorter interval could achieve a critical-level effect of reducing the incidence of anastomotic leakage (RR=0.73, 95%CI 0.52-1.03, P>0.05); (3) when the time cut-off point within 7-8 weeks, increased interval significantly was associated with the poor overall survival (HR=1.17, 95% CI 1.00-1.36, P<0.05). Secondary outcomes found that the shorter interval could significantly reduce the positive resection margin rate (RR=0.53, 95% CI 0.38-0.75, P<0.05) when time cut-off point within 56-60 days.Conclusion Shortening the interval between nCRT and surgery can reduce the operative mortality, the incidence of anastomotic leakage, long-term mortality risk, and positive resection margin rate. It is recommended that surgery should be performed as soon as possible after the patient's physical recovery, preferably no more than 7-8 weeks, which supports the current study recommendation (within 3-8 weeks after nCRT).

Citation： HE Feng, TIE Hongtao, LANG Weisi, LUO Jun, CHEN Dan, WU Qingchen, YANG Long. Timing of surgery for esophageal cancer patients after neoadjuvant chemoradiotherapy: A systematic review and meta-analysis. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2019, 26(11): 1125-1135. doi: 10.7507/1007-4848.201812066 Copy

1.	Siegel RL, Miller KD, et al. Cancer statistics. CA Cancer J Clin, 2016, 66(1): 7-30.
2.	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.
3.	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.
4.	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.
5.	Kataoka K, Nakamura K, Mizusawa J, et al. Surrogacy of progression-free survival (PFS) for overall survival (OS) in esophageal cancer trials with preoperative therapy: Literature-based meta-analysis. Eur J Surg Oncol, 2017, 43(10): 1956-1961.
6.	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.
7.	Ajani JA, D'Amico TA, Almhanna K, et al. Esophageal and esophagogastric junction cancers, version 1. J Natl Compr Canc Netw, 2015, 13(2): 194-227.
8.	Little AG, Lerut AE, Harpole DH, et al. The Society of Thoracic Surgeons practice guidelines on the role of multimodality treatment for cancer of the esophagus and gastroesophageal junction. Ann Thorac Surg, 2014, 98(5): 1880-1885.
9.	Kathiravetpillai N, Koëter M, van der Sangen MJ, et al. Delaying surgery after neoadjuvant chemoradiotherapy does not significantly influence postoperative morbidity or oncological outcome in patients with oesophageal adenocarcinoma. Eur J Surg Oncol, 2016, 42(8): 1183-1190.
10.	Burmeister BH, Smithers BM, Gebski V, et al. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase Ⅲ trial. Lancet Oncol, 2005, 6(9): 659-668.
11.	Tessier W, Gronnier C, Messager M, et al. Does timing of surgical procedure after neoadjuvant chemoradiation affect outcomes in esophageal cancer? Ann Thorac Surg, 2014, 97(4): 1181-1189.
12.	Tulchinsky H, Shmueli E, Figer A, et al. An interval >7 weeks between neoadjuvant therapy and surgery improves pathologic complete response and disease-free survival in patients with locally advanced rectal cancer. Ann Surg Oncol, 2008, 15(10): 2661-2667.
13.	Kalady MF, de Campos-Lobato LF, Stocchi L, et al. Predictive factors of pathologic complete response after neoadjuvant chemoradiation for rectal cancer. Ann Surg, 2009, 250(4): 582-589.
14.	Hanna A, Chuong MD, Søren BM, et al. An analysis of treatment timing parameters for patients receiving neoadjuvant chemoradiation followed by surgery for esophageal adenocarcinoma: A national cancer data base study. J Am Coll Surg, 2015, 221: e126.
15.	Lee A, Wong AT, Schwartz D, et al. Is there a benefit to prolonging the interval between neoadjuvant chemoradiation and esophagectomy in esophageal cancer? Ann Thorac Surg, 2016, 102(2): 433-438.
16.	Probst CP, Aquina CT, Hensley BJ, et al. Is more patience required between time from neoadjuvant therapy to esophagectomy? J Am Coll Surg, 2015, 221(14): S150.
17.	Shaikh T, Ruth K, Scott WJ, et al. Increased time from neoadjuvant chemoradiation to surgery is associated with higher pathologic complete response rates in esophageal cancer. Ann Thorac Surg, 2015, 99(1): 270-276.
18.	Shapiro J, van Hagen P, Lingsma HF, et al. Prolonged time to surgery after neoadjuvant chemoradiotherapy increases histopathological response without affecting survival in patients with esophageal or junctional cancer. Ann Surg, 2014, 260(5): 807-813.
19.	Ruol A, Rizzetto C, Castoro C, et al. Interval between neoadjuvant chemoradiotherapy and surgery for squamous cell carcinoma of the thoracic esophagus: does delayed surgery have an impact on outcome? Ann Surg, 2010, 252(5): 788-796.
20.	Franko J, Voynov G, Goldman CD. Esophagectomy timing after neoadjuvant therapy for distal esophageal adenocarcinoma. Ann Thorac Surg, 2016, 101(3): 1123-1130.
21.	Chiu CH, Chao YK, Chang HK, et al. Interval between neoadjuvant chemoradiotherapy and surgery for esophageal squamous cell carcinoma: does delayed surgery impact outcome? Ann Surg Oncol, 2013, 20(13): 4245-4251.
22.	Teman NR, Silski L, Zhao L, et al. Delaying surgery for esophageal cancer increases postoperative complications. J Am Coll Surg, 2013, 217: S35-S36.
23.	Roh S, Iannettoni M, Keech J, et al. Timing of esophagectomy after neoadjuvant chemoradiation therapy affects clinically significant anastomotic leak rates. Ann Surg Oncol, 2016, 23: S150.
24.	Parekh KFT, Van Natta T, Lynch W, et al. Timing of esophagectomy after completion of neoadjuvant therapy affects anastomotic leak rates. Interac Cardiovasc Thoracic Surg, 2008: S185.
25.	Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group. JAMA, 2000, 283(15): 2008-2012.
26.	Wells GA, Shea B, O'Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 3rd Symposium on Systematic Reviews: Beyond the Basics, Oxford, UK, 2000. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm.
27.	Kim JY, Correa AM, Vaporciyan AA, et al. Does the timing of esophagectomy chemoradiation affect outcome? Ann Thorac Surg, 2012, 93(1): 207-213.
28.	Singla S, Kukar M, Alnaji RM, et al. Complete pathologic response is independent of the timing of esophagectomy and is predictive of improved survival following neoadjuvant chemoradiation for esophageal cancer. Ann Surg Oncol, 2015, 22: S14.
29.	Wang BY, Chen HS, Hsu PK, et al. Clinical impact of the interval between chemoradiotherapy and esophagectomy in esophageal squamous cell carcinoma patients. Ann Thorac Surg, 2015, 99(3): 947-955.
30.	Haisley KR, Laird AE, Nabavizadeh N, et al. Association of intervals between neoadjuvant chemoradiation and surgical resection with pathologic complete response and survival in patients with esophageal cancer. JAMA Surg, 2016, 151(11): e162743.
31.	Tsang JS, Tong DKH, Lam KO, et al. Appropriate timing for surgery after neoadjuvant chemoradiation for esophageal cancer. Dis Esophagus, 2017, 30(9): 1-8.
32.	Singla S, Gabriel E, Alnaji R, et al. Complete pathologic response is independent of the timing of esophagectomy following neoadjuvant chemoradiation for esophageal cancer. J Gastrointest Oncol, 2018, 9(1): 73-79.
33.	Ranney, DN, Mulvihill MS, Yerokun BA, et al. Surgical resection after neoadjuvant chemoradiation for oesophageal adenocarcinoma: what is the optimal timing? Eur J Cardiothorac Surg, 2017, 52(3): 543-551.
34.	van der Werf LR, Dikken JL, van der Willik EM, et al. Time interval between neoadjuvant chemoradiotherapy and surgery for oesophageal or junctional cancer: A nationwide study. Eur J Cancer, 2018, 91: 76-85.
35.	Delanian S, Lefaix JL. Current management for late normal tissue injury: radiation-induced fibrosis and necrosis. Semin Radiat Oncol, 2007, 17(2): 99-107.
36.	Foster JD, Jones EL, Falk S, et al. Timing of surgery after long-course neoadjuvant chemoradiotherapy for rectal cancer: a systematic review of the literature. Dis Colon Rectum, 2013, 56(7): 921-930.
37.	Kerr SF, Norton S, Glynne-Jones R. Delaying surgery after neoadjuvant chemoradiotherapy for rectal cancer may reduce postoperative morbidity without compromising prognosis. Br J Surg, 2008, 95(12): 1534-1540.

1. Siegel RL, Miller KD, et al. Cancer statistics. CA Cancer J Clin, 2016, 66(1): 7-30.
2. 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.
3. 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.
4. 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.
5. Kataoka K, Nakamura K, Mizusawa J, et al. Surrogacy of progression-free survival (PFS) for overall survival (OS) in esophageal cancer trials with preoperative therapy: Literature-based meta-analysis. Eur J Surg Oncol, 2017, 43(10): 1956-1961.
6. 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.
7. Ajani JA, D'Amico TA, Almhanna K, et al. Esophageal and esophagogastric junction cancers, version 1. J Natl Compr Canc Netw, 2015, 13(2): 194-227.
8. Little AG, Lerut AE, Harpole DH, et al. The Society of Thoracic Surgeons practice guidelines on the role of multimodality treatment for cancer of the esophagus and gastroesophageal junction. Ann Thorac Surg, 2014, 98(5): 1880-1885.
9. Kathiravetpillai N, Koëter M, van der Sangen MJ, et al. Delaying surgery after neoadjuvant chemoradiotherapy does not significantly influence postoperative morbidity or oncological outcome in patients with oesophageal adenocarcinoma. Eur J Surg Oncol, 2016, 42(8): 1183-1190.
10. Burmeister BH, Smithers BM, Gebski V, et al. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase Ⅲ trial. Lancet Oncol, 2005, 6(9): 659-668.
11. Tessier W, Gronnier C, Messager M, et al. Does timing of surgical procedure after neoadjuvant chemoradiation affect outcomes in esophageal cancer? Ann Thorac Surg, 2014, 97(4): 1181-1189.
12. Tulchinsky H, Shmueli E, Figer A, et al. An interval >7 weeks between neoadjuvant therapy and surgery improves pathologic complete response and disease-free survival in patients with locally advanced rectal cancer. Ann Surg Oncol, 2008, 15(10): 2661-2667.
13. Kalady MF, de Campos-Lobato LF, Stocchi L, et al. Predictive factors of pathologic complete response after neoadjuvant chemoradiation for rectal cancer. Ann Surg, 2009, 250(4): 582-589.
14. Hanna A, Chuong MD, Søren BM, et al. An analysis of treatment timing parameters for patients receiving neoadjuvant chemoradiation followed by surgery for esophageal adenocarcinoma: A national cancer data base study. J Am Coll Surg, 2015, 221: e126.
15. Lee A, Wong AT, Schwartz D, et al. Is there a benefit to prolonging the interval between neoadjuvant chemoradiation and esophagectomy in esophageal cancer? Ann Thorac Surg, 2016, 102(2): 433-438.
16. Probst CP, Aquina CT, Hensley BJ, et al. Is more patience required between time from neoadjuvant therapy to esophagectomy? J Am Coll Surg, 2015, 221(14): S150.
17. Shaikh T, Ruth K, Scott WJ, et al. Increased time from neoadjuvant chemoradiation to surgery is associated with higher pathologic complete response rates in esophageal cancer. Ann Thorac Surg, 2015, 99(1): 270-276.
18. Shapiro J, van Hagen P, Lingsma HF, et al. Prolonged time to surgery after neoadjuvant chemoradiotherapy increases histopathological response without affecting survival in patients with esophageal or junctional cancer. Ann Surg, 2014, 260(5): 807-813.
19. Ruol A, Rizzetto C, Castoro C, et al. Interval between neoadjuvant chemoradiotherapy and surgery for squamous cell carcinoma of the thoracic esophagus: does delayed surgery have an impact on outcome? Ann Surg, 2010, 252(5): 788-796.
20. Franko J, Voynov G, Goldman CD. Esophagectomy timing after neoadjuvant therapy for distal esophageal adenocarcinoma. Ann Thorac Surg, 2016, 101(3): 1123-1130.
21. Chiu CH, Chao YK, Chang HK, et al. Interval between neoadjuvant chemoradiotherapy and surgery for esophageal squamous cell carcinoma: does delayed surgery impact outcome? Ann Surg Oncol, 2013, 20(13): 4245-4251.
22. Teman NR, Silski L, Zhao L, et al. Delaying surgery for esophageal cancer increases postoperative complications. J Am Coll Surg, 2013, 217: S35-S36.
23. Roh S, Iannettoni M, Keech J, et al. Timing of esophagectomy after neoadjuvant chemoradiation therapy affects clinically significant anastomotic leak rates. Ann Surg Oncol, 2016, 23: S150.
24. Parekh KFT, Van Natta T, Lynch W, et al. Timing of esophagectomy after completion of neoadjuvant therapy affects anastomotic leak rates. Interac Cardiovasc Thoracic Surg, 2008: S185.
25. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group. JAMA, 2000, 283(15): 2008-2012.
26. Wells GA, Shea B, O'Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 3rd Symposium on Systematic Reviews: Beyond the Basics, Oxford, UK, 2000. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm.
27. Kim JY, Correa AM, Vaporciyan AA, et al. Does the timing of esophagectomy chemoradiation affect outcome? Ann Thorac Surg, 2012, 93(1): 207-213.
28. Singla S, Kukar M, Alnaji RM, et al. Complete pathologic response is independent of the timing of esophagectomy and is predictive of improved survival following neoadjuvant chemoradiation for esophageal cancer. Ann Surg Oncol, 2015, 22: S14.
29. Wang BY, Chen HS, Hsu PK, et al. Clinical impact of the interval between chemoradiotherapy and esophagectomy in esophageal squamous cell carcinoma patients. Ann Thorac Surg, 2015, 99(3): 947-955.
30. Haisley KR, Laird AE, Nabavizadeh N, et al. Association of intervals between neoadjuvant chemoradiation and surgical resection with pathologic complete response and survival in patients with esophageal cancer. JAMA Surg, 2016, 151(11): e162743.
31. Tsang JS, Tong DKH, Lam KO, et al. Appropriate timing for surgery after neoadjuvant chemoradiation for esophageal cancer. Dis Esophagus, 2017, 30(9): 1-8.
32. Singla S, Gabriel E, Alnaji R, et al. Complete pathologic response is independent of the timing of esophagectomy following neoadjuvant chemoradiation for esophageal cancer. J Gastrointest Oncol, 2018, 9(1): 73-79.
33. Ranney, DN, Mulvihill MS, Yerokun BA, et al. Surgical resection after neoadjuvant chemoradiation for oesophageal adenocarcinoma: what is the optimal timing? Eur J Cardiothorac Surg, 2017, 52(3): 543-551.
34. van der Werf LR, Dikken JL, van der Willik EM, et al. Time interval between neoadjuvant chemoradiotherapy and surgery for oesophageal or junctional cancer: A nationwide study. Eur J Cancer, 2018, 91: 76-85.
35. Delanian S, Lefaix JL. Current management for late normal tissue injury: radiation-induced fibrosis and necrosis. Semin Radiat Oncol, 2007, 17(2): 99-107.
36. Foster JD, Jones EL, Falk S, et al. Timing of surgery after long-course neoadjuvant chemoradiotherapy for rectal cancer: a systematic review of the literature. Dis Colon Rectum, 2013, 56(7): 921-930.
37. Kerr SF, Norton S, Glynne-Jones R. Delaying surgery after neoadjuvant chemoradiotherapy for rectal cancer may reduce postoperative morbidity without compromising prognosis. Br J Surg, 2008, 95(12): 1534-1540.

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Timing of surgery for esophageal cancer patients after neoadjuvant chemoradiotherapy: A systematic review and meta-analysis

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