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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.

ABSTRACT: 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.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.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.ClinicalTrials.gov Identifier: NCT01591135 . Registered 18 April 2012.

SUBMITTER: Chen Y

PROVIDER: S-EPMC5828310 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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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.

Chen Yun Y Zhu Zhengfei Z Zhao Weixin W Li Ling L Ye Jinjun J Wu Chaoyang C Tang Huarong H Lin Qin Q Li Jiancheng J Xia Yi Y Li Yunhai Y Zhou Jialiang J Zhao Kuaile K

Radiation oncology (London, England) 20180227 1

<h4>Background</h4>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 ...[more]

PMID: 29482649

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Project description:PURPOSE:This trial aimed to assess the efficacy and safety of the paclitaxel plus fluorouracil regimen versus the cisplatin plus fluorouracil regimen in definitive concurrent chemoradiotherapy (dCRT) in patients with locally advanced esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS:Patients with locally advanced ESCC were enrolled and randomly assigned to either the paclitaxel plus fluorouracil group or the cisplatin plus fluorouracil group. The patients in the paclitaxel plus fluorouracil group were treated with paclitaxel and fluorouracil one cycle per week in dCRT for five cycles followed by paclitaxel and fluorouracil one cycle per month in consolidation chemotherapy for two cycles. The patients in the cisplatin/5-fluorouracil group were treated with cisplatin and fluorouracil one cycle per month in dCRT for two cycles followed by two cycles in consolidation chemotherapy. The radiotherapy dose was 61.2 Gy delivered in 34 fractions. The primary end point was 3-year overall survival (OS). RESULTS:Four hundred thirty-six patients with ESCC in six centers were recruited at a 1:1 ratio between April 2012 and July 2015. The median follow-up of the surviving patients was 48.7 months (interquartile range, 42.6-60.9). The 3-year OS was 55.4% in the paclitaxel plus fluorouracil group and 51.8% in the cisplatin plus fluorouracil group (hazard ratio, 0.905 [95% CI, 0.698 to 1.172]; P = .448). The 3-year progression-free survival was also not significantly different between the paclitaxel plus fluorouracil group and the cisplatin plus fluorouracil group (43.7% v 45.5%, respectively; hazard ratio, 0.973 [95% CI, 0.762 to 1.243]; P = .828). Compared with the cisplatin plus fluorouracil group, the paclitaxel plus fluorouracil group had significantly lower incidences of acute grade 3 or higher anemia, thrombocytopenia, anorexia, nausea, vomiting, and fatigue (P < .05), but higher incidences of acute grade 3 or higher leukopenia, radiation dermatitis, and radiation pneumonitis (P < .05). CONCLUSION:The paclitaxel plus fluorouracil regimen did not significantly prolong the OS compared with the standard cisplatin plus fluorouracil regimen in dCRT in patients with locally advanced ESCC.

Project description:BackgroundTo compare the efficacy and safety of postoperative extensive target volume irradiation with elevated radiation dose and concurrent chemotherapy with radiotherapy only for the postoperative treatment of esophageal squamous cell carcinoma.MethodsThis trial was a single-arm phase II trial. Patients who underwent a radical transthoracic resection with negative margins within 3 months and histologically confirmed esophageal squamous cell carcinoma (pT3-4N0M0 or pTxN + M0, AJCC 7th) were eligible for this study. Postoperative radiotherapy was performed at a total dose of 45 Gy in 25 fractions with clinical target volumes of the tumor bed, anastomosis, bilateral supraclavicular, mediastinal, left gastric and celiac trunk lymph node areas. Five cycles of weekly TC (paclitaxel 50 mg/m2, d1, carboplatin AUC = 2, d1) were given as concurrent chemotherapy. The primary endpoint was the 2-year local control rate, and the secondary endpoints were overall survival, disease free survival, local-regional recurrence free survival, distant metastasis free survival and adverse events. All endpoints were compared with those in ESO-Shanghai 8 study with postoperative radiotherapy alone (40 Gy/20Fx).ResultsA total of 70 patients were enrolled from 2016 to 2018. The 2-year local control rate was 87.9% (95% CI: 83.3-92.3) in this study, which achieved the hypothesized 2-year local control rate of at least 83%. Overall survival, disease free survival, local-regional recurrence free survival and distant metastasis free survival in this study were also longer than those in previous ESO-Shanghai 8 study while most toxicities were increased and two patients in this study died of radiation pneumonitis.ConclusionsPostoperative extensive target volume irradiation with elevated radiation dose and concurrent chemotherapy was effective. Treatment related toxicity was increased due to higher treatment intensity. Trial registration clinicaltrials.gov: NCT02916511.

Project description:INTRODUCTION:Concurrent chemoradiation is the standard therapy for patients with local advanced oesophageal carcinoma unsuitable for surgery. Paclitaxel is an active agent against oesophageal cancer and it has been proved as a potent radiation sensitiser. There have been multiple studies evaluating paclitaxel-based chemoradiation in oesophageal cancer, of which the results are inspiring. However, which regimen, among cisplatin (TP), carboplatin (TC) or fluorouracil (TF) in combination with paclitaxel concurrent with radiotherapy, provides best prognosis with minimum adverse events is still unknown and very few studies focus on this field. The purpose of this study is to confirm the priority of TF to TP or TF to TC concurrent with radiotherapy in terms of overall survival and propose a feasible and effective plan for patients with local advanced oesophageal cancer. METHODS AND ANALYSIS:ESO-Shanghai 2 is a three-arm, multicenter, open-labelled, randomised phase III clinical trial. The study was initiated in July 2015 and the duration of inclusion is expected to be 4 years. The study compares two pairs of regimen: TF versus TP and TF versus TC concurrent with definitive radiotherapy for patients with oesophageal squamous cell carcinoma (OSCC). Patients with histologically confirmed OSCC (clinical stage II, III or IVa based on the sixth Union for International Cancer Control-tumour, node, metastasis classification) and without any prior treatment of chemotherapy, radiotherapy or surgery against oesophageal cancer will be eligible. A total of 321 patients will be randomised and allocated in a 1:1:1 ratio to the three treatment groups. Patients are stratified by lymph node status (N0, N1, M1a). The primary endpoint is overall survival and the secondary endpoint is progression-free survival and adverse events. ETHICS AND DISSEMINATION:This trial has been approved by the Fudan University Shanghai Cancer Centre Institutional Review Board. Trial results will be disseminated via peer reviewed scientific journals and conference presentations. TRIAL STATUS:The trial was initiated in July 2015 and is currently recruiting patients in all of the participating institutions above. TRIAL REGISTRATION NUMBER:NCT02459457.

Project description:ImportanceMultiple paclitaxel-based regimens are widely used in chemoradiation therapy against esophageal cancer, including regimens combining paclitaxel with fluorouracil, cisplatin, and carboplatin. However, which among these 3 regimens provides the best prognosis with minimum adverse events is still unknown.ObjectiveTo compare the efficacy and adverse events of fluorouracil, cisplatin, and carboplatin in definitive chemoradiotherapy in patients with esophageal squamous cell carcinoma (ESCC).Design, setting, and participantsThis randomized clinical trial of patients with ESCC was conducted in 11 treatment centers in China. Eligible patients were aged 18 to 75 years and had histologically confirmed ESCC stages IIa to IVa with no prior treatment, Eastern Cooperative Oncology Group performance status of 2 or lower, and adequate organ functions. The study was conducted between July 2015 and February 2018, and the cutoff date for data analysis was August 31, 2020.InterventionsPatients with locally advanced ESCC were randomly assigned (1:1:1) to groups combining paclitaxel treatment with fluorouracil, cisplatin, or carboplatin. Patients in the cisplatin group were treated with 2 cycles of concurrent chemoradiotherapy followed by 2 cycles of consolidation chemotherapy with monthly paclitaxel plus cisplatin. For the fluorouracil group, patients were administered 6 cycles of weekly paclitaxel plus fluorouracil in concurrent chemoradiotherapy followed by 2 cycles of monthly paclitaxel plus fluorouracil in consolidation chemotherapy. Patients in the carboplatin group were treated with 6 cycles of weekly paclitaxel plus carboplatin in concurrent chemoradiotherapy followed by 2 cycles of monthly paclitaxel plus carboplatin in consolidation chemotherapy. All patients received radiotherapy of 61.2 Gy delivered in 34 fractions.Main outcomes and measuresThe primary end point was overall survival (OS). The secondary end points were progression-free survival and adverse events.ResultsOverall, 321 patients (median [IQR] age, 64 years [59-69 years]; 248 [77.3%] men) with ESCC from 11 centers were randomized into fluorouracil, cisplatin, or carboplatin groups between July 2015 and February 2018. Over a median (IQR) follow-up time of surviving patients of 46.0 months (36.6-53.0 months), the 3-year OS rates were 57.2% in the fluorouracil group, 60.1% in the cisplatin group, and 56.5% in the carboplatin group, respectively (fluorouracil vs cisplatin: HR, 1.06; 95% CI, 0.71-1.60; P = .77; fluorouracil vs carboplatin: HR, 0.94; 95% CI, 0.63-1.40; P = .77). The cisplatin group had significantly higher incidences of acute grade 3 or 4 neutropenia (69 events [60.8%] vs 19 [17.8%] for fluorouracil and 37 [34.6%] carboplatin; P < .001), thrombocytopenia (14 events [13.1%] vs 4 [3.7%] for fluorouracil and 5 [4.7%] for carboplatin; P = .01), anemia (50 events above grade 2 [46.7%] vs 25 [23.4%] for fluorouracil and 37 [34.6%] for carboplatin; P = .35), fatigue (11 events [10.3%] vs 2 [1.9%] for fluorouracil and 1 [0.9%] carboplatin; P = .007), and vomiting (17 events above grade 2 [15.9%] vs 3 [2.8%] for fluorouracil and 5 [4.7%] for carboplatin; P < .001) than the other 2 groups.Conclusions and relevanceIn this randomized clinical trial, paclitaxel plus fluorouracil did not show OS superiority over paclitaxel plus cisplatin or paclitaxel plus carboplatin regimens in definitive chemoradiation in patients with locally advanced ESCC. Higher rates of hematologic and gastrointestinal toxic effects were reported in the cisplatin group compared with those in the fluorouracil or carboplatin groups.Trial registrationClinicalTrials.gov Identifier: NCT02459457.

Dataset Information

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.

Publications

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.

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