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

Hong Yang, Hui Liu, Yuping Chen, Chengchu Zhu, Wentao Fang, Zhentao Yu, Weimin Mao, Jiaqing Xiang, Yongtao Han, Zhijian Chen, Haihua Yang, Jiaming Wang, Qingsong Pang, Xiao Zheng, Huanjun Yang, Tao Li, Florian Lordick, Xavier Benoit D'Journo, Robert J Cerfolio, Robert J Korst, Nuria M Novoa, Scott J Swanson, Alessandro Brunelli, Mahmoud Ismail, Hiran C Fernando, Xu Zhang, Qun Li, Geng Wang, Baofu Chen, Teng Mao, Min Kong, Xufeng Guo, Ting Lin, Mengzhong Liu, Jianhua Fu, AME Thoracic Surgery Collaborative Group, Hong Yang, Hui Liu, Yuping Chen, Chengchu Zhu, Wentao Fang, Zhentao Yu, Weimin Mao, Jiaqing Xiang, Yongtao Han, Zhijian Chen, Haihua Yang, Jiaming Wang, Qingsong Pang, Xiao Zheng, Huanjun Yang, Tao Li, Florian Lordick, Xavier Benoit D'Journo, Robert J Cerfolio, Robert J Korst, Nuria M Novoa, Scott J Swanson, Alessandro Brunelli, Mahmoud Ismail, Hiran C Fernando, Xu Zhang, Qun Li, Geng Wang, Baofu Chen, Teng Mao, Min Kong, Xufeng Guo, Ting Lin, Mengzhong Liu, Jianhua Fu, AME Thoracic Surgery Collaborative Group

Abstract

Purpose The efficacy of neoadjuvant chemoradiotherapy (NCRT) plus surgery for locally advanced esophageal squamous cell carcinoma (ESCC) remains controversial. In this trial, we compared the survival and safety of NCRT plus surgery with surgery alone in patients with locally advanced ESCC. Patients and Methods From June 2007 to December 2014, 451 patients with potentially resectable thoracic ESCC, clinically staged as T1-4N1M0/T4N0M0, were randomly allocated to NCRT plus surgery (group CRT; n = 224) and surgery alone (group S; n = 227). In group CRT, patients received vinorelbine 25 mg/m2 intravenously (IV) on days 1 and 8 and cisplatin 75 mg/m2 IV day 1, or 25 mg/m2 IV on days 1 to 4 every 3 weeks for two cycles, with a total concurrent radiation dose of 40.0 Gy administered in 20 fractions of 2.0 Gy on 5 days per week. In both groups, patients underwent McKeown or Ivor Lewis esophagectomy. The primary end point was overall survival. Results The pathologic complete response rate was 43.2% in group CRT. Compared with group S, group CRT had a higher R0 resection rate (98.4% v 91.2%; P = .002), a better median overall survival (100.1 months v 66.5 months; hazard ratio, 0.71; 95% CI, 0.53 to 0.96; P = .025), and a prolonged disease-free survival (100.1 months v 41.7 months; hazard ratio, 0.58; 95% CI, 0.43 to 0.78; P < .001). Leukopenia (48.9%) and neutropenia (45.7%) were the most common grade 3 or 4 adverse events during chemoradiotherapy. Incidences of postoperative complications were similar between groups, with the exception of arrhythmia (group CRT: 13% v group S: 4.0%; P = .001). Peritreatment mortality was 2.2% in group CRT versus 0.4% in group S ( P = .212). Conclusion This trial shows that NCRT plus surgery improves survival over surgery alone among patients with locally advanced ESCC, with acceptable and manageable adverse events.

Trial registration: ClinicalTrials.gov NCT01216527.

Figures

Fig 1.
Fig 1.
CONSORT diagram. DFS, disease-free survival; ESCC, esophageal squamous cell carcinoma.
Fig 2.
Fig 2.
Overall survival and disease-free survival. (A) Overall survival in the intention-to-treat population. (B) Disease-free survival for patients after R0 resection. CRT, chemoradiotherapy; HR, hazard ratio; S, surgery alone.
Fig A1.
Fig A1.
Subgroup analysis. CRT, chemoradiotherapy; HR, hazard ratio.

References

    1. Jemal A, Bray F, Center MM, et al. : Global cancer statistics. CA Cancer J Clin 61:69-90, 2011
    1. Chen W, Zheng R, Baade PD, et al. : Cancer statistics in China, 2015. CA Cancer J Clin 66:115-132, 2016
    1. Herskovic A, Russell W, Liptay M, et al. : Esophageal carcinoma advances in treatment results for locally advanced disease: Review. Ann Oncol 23:1095-1103, 2012
    1. Sjoquist KM, Burmeister BH, Smithers BM, et al. : Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: An updated meta-analysis. Lancet Oncol 12:681-692, 2011
    1. Apinop C, Puttisak P, Preecha N: A prospective study of combined therapy in esophageal cancer. Hepatogastroenterology 41:391-393, 1994
    1. Walsh TN, Noonan N, Hollywood D, et al. : A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 335:462-467, 1996
    1. 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 19:305-313, 2001
    1. Lee JL, Park SI, Kim SB, et al. : A single institutional phase III trial of preoperative chemotherapy with hyperfractionation radiotherapy plus surgery versus surgery alone for resectable esophageal squamous cell carcinoma. Ann Oncol 15:947-954, 2004
    1. 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 6:659-668, 2005
    1. 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 26:1086-1092, 2008
    1. 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 16:1090-1098, 2015
    1. Mariette C, Dahan L, Mornex F, et al. : Surgery alone versus chemoradiotherapy followed by surgery for stage I and II esophageal cancer: Final analysis of randomized controlled phase III trial FFCD 9901. J Clin Oncol 32:2416-2422, 2014
    1. Lv J, Cao XF, Zhu B, et al. : Long-term efficacy of perioperative chemoradiotherapy on esophageal squamous cell carcinoma. World J Gastroenterol 16:1649-1654, 2010
    1. Greene FL, Page DL, Fleming ID. (eds): AJCC Cancer Staging Manual (ed 6). New York, NY, Springer-Verlag, 2002.
    1. Yang H, Fu JH, Hu Y, et al. : Neo-adjuvant chemoradiotherapy followed by surgery in treatment of advanced esophageal carcinoma [in Chinese]. Zhonghua Yi Xue Za Zhi 88:3182-3185, 2008
    1. Swanson SJ, Batirel HF, Bueno R, et al: Transthoracic esophagectomy with radical mediastinal and abdominal lymph node dissection and cervical esophagogastrostomy for esophageal carcinoma. Ann Thorac Surg 72:1918-1924; discussion 1924-1925, 2001.
    1. Fujita H, Kakegawa T, Yamana H, et al. : Lymph node metastasis and recurrence in patients with a carcinoma of the thoracic esophagus who underwent three-field dissection. World J Surg 18:266-272, 1994
    1. Sun HB, Li Y, Liu XB, et al. : Early oral feeding following McKeown minimally invasive esophagectomy: An open-label, randomized, controlled, noninferiority trial. Ann Surg 267:435-442, 2018
    1. 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 19:68-74, 2012
    1. Li B, Xiang J, Zhang Y, et al. : Comparison of Ivor-Lewis vs Sweet esophagectomy for esophageal squamous cell carcinoma: A randomized clinical trial. JAMA Surg 150:292-298, 2015
    1. The Society of Esophageal Cancer in Chinese Anti-Cancer Association : Guidelines for Standardized Diagnosis and Treatment of Esophageal Cancer. Peking, China, Peking Union Medical College Press, 2013
    1. National Comprehensive Cancer Network : NCCN Clinical Practice Guidelines in Oncology: Esophageal and Esophagogastric Junction Cancers, Version 2, 2018.
    1. Lordick F, Mariette C, Haustermans K, et al. : Oesophageal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 27(suppl 5):v50-v57, 2016
    1. Mulligan ED, Dunne B, Griffin M, et al. : Margin involvement and outcome in oesophageal carcinoma: A 10-year experience in a specialist unit. Eur J Surg Oncol 30:313-317, 2004
    1. Hofstetter W, Swisher SG, Correa AM, et al. : Treatment outcomes of resected esophageal cancer. Ann Surg 236:376-384, discussion 384-385, 2002
    1. Berger AC, Farma J, Scott WJ, et al. : Complete response to neoadjuvant chemoradiotherapy in esophageal carcinoma is associated with significantly improved survival. J Clin Oncol 23:4330-4337, 2005

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe