A randomized phase 3 trial comparing paclitaxel plus 5-fluorouracil versus cisplatin plus 5-fluorouracil in Chemoradiotherapy for locally advanced esophageal carcinoma-the ESO-shanghai 1 trial protocol

Yun Chen, Zhengfei Zhu, Weixin Zhao, Ling Li, Jinjun Ye, Chaoyang Wu, Huarong Tang, Qin Lin, Jiancheng Li, Yi Xia, Yunhai Li, Jialiang Zhou, Kuaile Zhao, Yun Chen, Zhengfei Zhu, Weixin Zhao, Ling Li, Jinjun Ye, Chaoyang Wu, Huarong Tang, Qin Lin, Jiancheng Li, Yi Xia, Yunhai Li, Jialiang Zhou, Kuaile Zhao

Abstract

Background: Concurrent chemoradiotherapy is a standard modality for locally advanced esophageal squamous cell carcinoma (ESCC) patients. Cisplatin combined with 5-fluorouracil continuous infusion (PF) remains the standard concurrent chemotherapy regimen. However, radiotherapy concurrent with PF showed a high incidence of severe side effects. Paclitaxel showed a promising radiosensitivity enhancement in the treatment of esophageal carcinoma in both vitro and vivo studies. The ESO-Shanghai 1 trial examines the hypothesis that paclitaxel plus 5-fluorouracil (TF) concurrent with radiotherapy has better overall survival and lower toxicity for patients with local advanced ESCC.

Method: Four hundred thirty-six ESCC patients presenting with stage IIa to IVa will be enrolled in a prospective multicenter randomized phase 3 study. Patients will be randomized to either concurrent chemoradiotherapy with PF (cisplatin 25 mg/m2/d, d1-3, plus 5-fluorouracil 1800 mg/m2, continuous infusion for 72 h) once every 4 weeks for 2 cycles followed by consolidation chemotherapy for 2 cycles or concurrent chemoradiotherapy with weekly TF (5-fluorouracil 300 mg/m2, continuous infusion for 96 h plus paclitaxel 50 mg/m2, d1) for 5 weeks followed by consolidation chemotherapy (5-fluorouracil 1800 mg/m2, continuous infusion for 72 h, plus paclitaxel 175 mg/m2 d1) once every 4 weeks for 2 cycles. The radiotherapy dose is 61.2 Gy delivered in 34 fractions to the primary tumor including lymph nodes. The primary end-point is the 3-yr overall survival analyzed by intention to treat. The secondary endpoints are disease progression-free survival, local progression-free survival, and number and grade of participants with adverse events.

Discussion: The aim of this phase 3 study is to determine whether the TF regimen could replace the standard PF regimen for inoperable ESCC patients. An overall survival benefit of 12% at 3 years should be expected in the TF group to achieve this goal.

Trial registration: ClinicalTrials.gov Identifier: NCT01591135 . Registered 18 April 2012.

Keywords: 5-fluorouracil; Cisplatin; Concurrent chemoradiotherapy; Esophageal squamous cell carcinoma; Paclitaxel.

Conflict of interest statement

Ethics approval and consent to participate

The final protocol was approved by the Ethics Committee of Fudan University Shanghai Cancer Center (1203108–4).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no financial or non-financial competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Trial diagram of the ESO-Shanghai 1 trial. 436 esophageal squamous cell carcinoma patients are randomized to either Arm A (concurrent chemoradiotherapy with the PF regimen for 2 cycles followed by consolidation chemotherapy for 2 cycles) or to Arm B (concurrent chemoradiotherapy with a weekly TF regimen for 5 weeks followed by consolidation chemotherapy for 2 cycles)
Fig. 2
Fig. 2
Treatment design of the ESO-Shanghai 1 trial. Patients in both Arms will receive concurrent chemoradiotherapy and consolidation chemotherapy. Radiotherapy will begin on Day 1, concurrent with the beginning of cycle 1 of chemotherapy. (Abbreviations: R, radiotherapy; PTX, paclitaxel; DDP (P), cisplatin; 5-FU (F), 5-fluorouracil; PF, cisplatin plus 5-fluorouracil; TF, paclitaxel plus 5-fluorouracil)

References

    1. Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA, Jr, Al-Sarraf M, Byhardt R, Russell AH, Beitler JJ, Spencer S, et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation therapy oncology group. JAMA. 1999;281(17):1623–1627. doi: 10.1001/jama.281.17.1623.
    1. Ajani JA, Ilson DH, Daugherty K, Pazdur R, Lynch PM, Kelsen DP. Activity of taxol in patients with squamous cell carcinoma and adenocarcinoma of the esophagus. J Natl Cancer Inst. 1994;86(14):1086–1091. doi: 10.1093/jnci/86.14.1086.
    1. Ilson DH, Wadleigh RG, Leichman LP, Kelsen DP. Paclitaxel given by a weekly 1-h infusion in advanced esophageal cancer. Ann Oncol. 2007;18(5):898–902. doi: 10.1093/annonc/mdm004.
    1. Milas L, Milas MM, Mason KA. Combination of taxanes with radiation: preclinical studies. Semin Radiat Oncol. 1999;9(2 Suppl 1):12–26.
    1. Tishler RB, Schiff PB, Geard CR, Hall EJ. Taxol: a novel radiation sensitizer. Int J Radiat Oncol Biol Phys. 1992;22(3):613–617. doi: 10.1016/0360-3016(92)90888-O.
    1. van Rijn J, van den Berg J, Meijer OW. Proliferation and clonal survival of human lung cancer cells treated with fractionated irradiation in combination with paclitaxel. Int J Radiat Oncol Biol Phys. 1995;33(3):635–639. doi: 10.1016/0360-3016(95)00216-L.
    1. Milas L, Hunter N, Mason KA, Milross C, Peters LJ. Tumor reoxygenation as a mechanism of taxol-induced enhancement of tumor radioresponse. Acta Oncol. 1995;34(3):409–412. doi: 10.3109/02841869509093999.
    1. Milas L, Hunter NR, Mason KA, Milross CG, Saito Y, Peters LJ. Role of reoxygenation in induction of enhancement of tumor radioresponse by paclitaxel. Cancer Res. 1995;55(16):3564–3568.
    1. Kelsey CR, Chino JP, Willett CG, Clough RW, Hurwitz HI, Morse MA, Bendell JC, D'Amico TA, Czito BG. Paclitaxel-based chemoradiotherapy in the treatment of patients with operable esophageal cancer. Int J Radiat Oncol Biol Phys. 2007;69(3):770–776. doi: 10.1016/j.ijrobp.2007.03.035.
    1. Weiner LM, Colarusso P, Goldberg M, Dresler C, Coia LR. Combined-modality therapy for esophageal cancer: phase I trial of escalating doses of paclitaxel in combination with cisplatin, 5-fluorouracil, and high-dose radiation before esophagectomy. Semin Oncol. 1997;24(6 Suppl 19):S19-93-S19-95.
    1. Wright CD, Wain JC, Lynch TJ, Choi NC, Grossbard ML, Carey RW, Moncure AC, Grillo HC, Mathisen DJ. Induction therapy for esophageal cancer with paclitaxel and hyperfractionated radiotherapy: a phase I and II study. J Thorac Cardiovasc Surg. 1997;114(5):811–815. doi: 10.1016/S0022-5223(97)70085-0.
    1. Adelstein DJ, Rice TW, Rybicki LA, Larto MA, Ciezki J, Saxton J, DeCamp M, Vargo JJ, Dumot JA, Zuccaro G. Does paclitaxel improve the chemoradiotherapy of locoregionally advanced esophageal cancer? A nonrandomized comparison with fluorouracil-based therapy. J Clin Oncol. 2000;18(10):2032–2039. doi: 10.1200/JCO.2000.18.10.2032.
    1. Thirion P, Piedbois Y. Preoperative chemoradiotherapy using taxanes for locally advanced esophageal carcinoma. J Clin Oncol. 2001;19(6):1880–1882. doi: 10.1200/JCO.2001.19.6.1880.
    1. Ajani JA, Winter K, Komaki R, Kelsen DP, Minsky BD, Liao Z, Bradley J, Fromm M, Hornback D, Willett CG. Phase II randomized trial of two nonoperative regimens of induction chemotherapy followed by chemoradiation in patients with localized carcinoma of the esophagus: RTOG 0113. J Clin Oncol. 2008;26(28):4551–4556. doi: 10.1200/JCO.2008.16.6918.
    1. Minsky BD, Pajak TF, Ginsberg RJ, Pisansky TM, Martenson J, Komaki R, Okawara G, Rosenthal SA, Kelsen DP. INT 0123 (radiation therapy oncology group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol. 2002;20(5):1167–1174. doi: 10.1200/JCO.2002.20.5.1167.
    1. Van Meter EM, Garrett-Mayer E, Bandyopadhyay D. Dose-finding clinical trial design for ordinal toxicity grades using the continuation ratio model: an extension of the continual reassessment method. Clinical trials. 2012;9(3):303–313. doi: 10.1177/1740774512443593.
    1. CHEN Y, Ai T, Xia Y, Liu Q, Zhang J, Zhao K. Results of a phase II study of concurrent 5-fluorouracil/paclitaxel plus radiotherapy in patients with carcinoma of the esophagus. China Oncol. 2016;26(11):926–931.
    1. Herskovic A, Martz K, al-Sarraf M, Leichman L, Brindle J, Vaitkevicius V, Cooper J, Byhardt R, Davis L, Emami B. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med. 1992;326(24):1593–1598. doi: 10.1056/NEJM199206113262403.
    1. Schnirer II, Komaki R, Yao JC, Swisher S, Putnam J, Pisters PW, Roth JA, Ajani JA. Pilot study of concurrent 5-fluorouracil/paclitaxel plus radiotherapy in patients with carcinoma of the esophagus and gastroesophageal junction. Am J Clin Oncol. 2001;24(1):91–95. doi: 10.1097/00000421-200102000-00018.
    1. van der Gaast A, Kok TC, Vos R, Kerkhofs L, Splinter TA. A phase I dose finding study of a biweekly schedule of a fixed dose of cisplatin with increasing doses of paclitaxel in patients with advanced esophageal cancer. Semin Oncol. 1997;24(6 Suppl 19):S19.
    1. Kelsen D, Ginsberg R, Bains M, Cooper J, Arquette M, Forastiere AA, Ilson D. A phase II trial of paclitaxel and cisplatin in patients with locally advanced metastatic esophageal cancer: a preliminary report. Semin Oncol. 1997;24(6 Suppl 19):S19-77-S19-81.
    1. Polee MB, Eskens FA, van der Burg ME, Splinter TA, Siersema PD, Tilanus HW, Verweij J, Stoter G, van der Gaast A. Phase II study of bi-weekly administration of paclitaxel and cisplatin in patients with advanced oesophageal cancer. Br J Cancer. 2002;86(5):669–673. doi: 10.1038/sj.bjc.6600166.
    1. Huang J, Cai RG, Meng PJ, Zhang MJ, Cui CX, Yang L, Chu DT, Sun Y, Wang JW. Phase II study of paclitaxel and cisplatin for advanced squamous-cell carcinoma of esophagus. Zhonghua Zhong Liu Za Zhi. 2004;26(12):753–755.
    1. Ilson DH, Ajani J, Bhalla K, Forastiere A, Huang Y, Patel P, Martin L, Donegan J, Pazdur R, Reed C, et al. Phase II trial of paclitaxel, fluorouracil, and cisplatin in patients with advanced carcinoma of the esophagus. J Clin Oncol. 1998;16(5):1826–1834. doi: 10.1200/JCO.1998.16.5.1826.
    1. Lin CC, Yeh KH, Yang CH, Hsu C, Tsai YC, Hsu WL, Cheng AL, Hsu CH. Multifractionated paclitaxel and cisplatin combined with 5-fluorouracil and leucovorin in patients with metastatic or recurrent esophageal squamous cell carcinoma. Anti-Cancer Drugs. 2007;18(6):703–708. doi: 10.1097/CAD.0b013e328051b3a3.
    1. Safran H, Gaissert H, Akerman P, Hesketh PJ, Chen MH, Moore T, Koness J, Graziano S, Wanebo HJ. Paclitaxel, cisplatin, and concurrent radiation for esophageal cancer. Cancer Investig. 2001;19(1):1–7. doi: 10.1081/CNV-100000068.
    1. Bains MS, Stojadinovic A, Minsky B, Rusch V, Turnbull A, Korst R, Ginsberg R, Kelsen DP, Ilson DH. A phase II trial of preoperative combined-modality therapy for localized esophageal carcinoma: initial results. J Thorac Cardiovasc Surg. 2002;124(2):270–277. doi: 10.1067/mtc.2002.122545.
    1. Urba SG, Orringer MB, Ianettonni M, Hayman JA, Satoru H. Concurrent cisplatin, paclitaxel, and radiotherapy as preoperative treatment for patients with locoregional esophageal carcinoma. Cancer. 2003;98(10):2177–2183. doi: 10.1002/cncr.11759.
    1. van Meerten E, Muller K, Tilanus HW, Siersema PD, Eijkenboom WM, van Dekken H, Tran TC, van der Gaast A. Neoadjuvant concurrent chemoradiation with weekly paclitaxel and carboplatin for patients with oesophageal cancer: a phase II study. Br J Cancer. 2006;94(10):1389–1394. doi: 10.1038/sj.bjc.6603134.
    1. Meluch AA, Greco FA, Gray JR, Thomas M, Sutton VM, Davis JL, Kalman LA, Shaffer DW, Yost K, Rinaldi DA, et al. Preoperative therapy with concurrent paclitaxel/carboplatin/infusional 5-FU and radiation therapy in locoregional esophageal cancer: final results of a Minnie pearl cancer research network phase II trial. Cancer J. 2003;9(4):251–260. doi: 10.1097/00130404-200307000-00007.
    1. Lin CC, Hsu CH, Cheng JC, Wang HP, Lee JM, Yeh KH, Yang CH, Lin JT, Cheng AL, Lee YC. Concurrent chemoradiotherapy with twice weekly paclitaxel and cisplatin followed by esophagectomy for locally advanced esophageal cancer. Ann Oncol. 2007;18(1):93–98. doi: 10.1093/annonc/mdl339.
    1. Jatoi A, Martenson JA, Foster NR, McLeod HL, Lair BS, Nichols F, Tschetter LK, Moore DF, Jr, Fitch TR, Alberts SR, et al. Paclitaxel, carboplatin, 5-fluorouracil, and radiation for locally advanced esophageal cancer: phase II results of preliminary pharmacologic and molecular efforts to mitigate toxicity and predict outcomes: north central cancer treatment group (N0044) Am J Clin Oncol. 2007;30(5):507–513. doi: 10.1097/COC.0b013e31805c139a.
    1. Roof KS, Coen J, Lynch TJ, Wright C, Fidias P, Willett CG, Choi NC. Concurrent cisplatin, 5-FU, paclitaxel, and radiation therapy in patients with locally advanced esophageal cancer. Int J Radiat Oncol Biol Phys. 2006;65(4):1120–1128. doi: 10.1016/j.ijrobp.2006.02.013.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi