Patient selection and study design
The ESWN 01 was a prospective randomized, multicenter, open-label, phase 3 trial performed at 15 participating centers across China. The inclusion criteria were as follows: (i) patients between the age 18–70 years, (ii) had histological confirmation of metastatic or recurrent ESCC (staged using the seventh edition of the American Joint Committee on Cancer [AJCC] staging manual since enrolment ended in July 2016), (iii) had disease progression after platinum-based or taxane-based chemotherapy, (iv) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, (v) had measurable disease as per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST version 1.1), and (vi) had adequate marrow and organ functions (assessed by the white blood cell, neutrophil, and platelet counts, measurement of hemoglobin concentration, and liver and kidney function tests). Patients were excluded if they had (i) previous treatments with irinotecan, fluorouracil, or any targeted or immunotherapy agents in a palliative setting, (ii) fluorouracil-based adjuvant chemotherapy within 6 months before the randomization, and (iii) cerebral or meningeal metastases. The data of patients’ prior lines of chemotherapy were collected.
The protocol was approved by the institutional review board and ethics committee at each institution. All recruited patients provided written informed consent before enrolment. This trial was performed in accordance with the principles of the Declaration of Helsinki and the Good Clinical Practice Guidelines of the International Conference on Harmonization and was registered at ClinicalTrials.gov, identifier: (identifier: NCT02319187).
Randomization and masking
Patients were randomly allocated in a 1:1 ratio to either the irinotecan plus S-1 group or the S-1 monotherapy group, using a central computerized minimization procedure. The randomization was stratified by age (> 65 vs. ≤ 65 years), ECOG performance status (0–1 vs. 2), tumor differentiation (poorly vs. moderately/well differentiated), and the extent of disease (recurrent vs. metastatic). The patients, investigators, and other trial staff were all aware of the treatment allocations after randomization.
Treatment procedures
In the irinotecan plus S-1 group, the patients received intravenous infusion of irinotecan (Jiangsu Hengrui Medicine Co. Ltd, Jiangsu, P.R. China) 160 mg/m2 on day 1, followed by oral S-1 (Jiangsu Hengrui Medicine Co. Ltd) 80–120 mg/day, on days 1–10, repeated every 14 days. In the S-1 monotherapy group, oral S-1 was prescribed at 80–120 mg/day on days 1–14, repeated every 21 days. The treatment doses and schedule in this study were based on the efficacy and safety data from our previous retrospective study on ESCC [14]. All patients received the allocated treatment until disease progression, intolerable adverse events, or withdrawal of consent.
Dose modifications due to treatment-related adverse events were allowed in this trial. If any patient developed grade 3 thrombocytopenia or other grade 4 hematologic adverse events related to the use of irinotecan, as assessed by the investigator, the dose of irinotecan was reduced by 20 mg/m2 each time to a minimum of 120 mg/m2 in the successive cycles. For patients developing grade 3 diarrhea related to irinotecan, the dose of irinotecan was reduced by 20 mg/m2 each time to a minimum of 100 mg/m2. For patients developing grade 3 nausea or diarrhea related to S-1, the dose of S-1 was reduced by 20 mg in the successive cycle. Granulocyte colony-stimulating factor (G-CSF) was administered to those who developed grade 3/4 neutropenia or leucopenia, whereas the prophylactic use of G-CSF was not allowed. Other anti-tumor treatments were not permitted during the study period. The post-study treatment (palliative radiation, systemic treatments) to be provided for those patients who experienced treatment failure was decided by the physician in charge at each respective institution and was not preplanned in the study design.
Treatment follow-up and safety
Scheduled visits and computed tomography (CT) scans of the chest and abdomen were repeated every 6 weeks until the onset of progressive disease. The tumor response was assessed by independent central radiologic review based on the RECIST criteria, version 1.1.
Treatment safety was monitored throughout the treatment and for 30 days after the last prescribed study dose. Symptoms developed during the study treatment were recorded, and physical examinations were performed at each scheduled visit. A complete blood count (CBC) test was repeated every week, and a blood chemistry test was repeated every month starting from the first dose of the study drug to detect potential adverse events and guide dose modifications as per the study protocol. Other clinical tests including urine, fecal occult blood, coagulation, and electrocardiogram were repeated when necessary as decided by the investigators. All adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE; version 4.02). After completion of the treatments, patients were followed up every 8 weeks until death. The post-study follow-up data were also collected.
Study outcomes
The primary endpoint was progression-free survival (PFS), defined as the time from randomization to radiographic progression, or death from any cause. Secondary endpoints included objective response rate (ORR), defined as the percentage of patients who had the best treatment response, either a radiological complete response or partial response; disease control rate (DCR), defined as the percentage of patients who had the best response of complete response, partial response, or stable disease. Other secondary endpoints included the duration of response, defined as the time from the first documentation of complete or partial response to radiological disease progression, and OS, defined as the time from randomization to death from any cause.
Statistical analysis
Before the start of the study, we assumed that patients were to be recruited over an 18-month period and were to be followed-up for a minimum of 6 months. To achieve a 90% power to detect an improvement in PFS from 2.5 months in the S-1 monotherapy group to 4.0 months in the irinotecan plus S-1 group, by accounting for a 20% loss due to follow-up with a two-sided α of 0.05, 228 patients had to be randomly assigned. The primary endpoint was analyzed in the intention-to-treat population, defined as all enrolled patients who were randomly assigned to a group, regardless of whether they received the study treatment.
Chi square or Fisher’s exact tests were used to compare the patient characteristics, ORRs, and DCRs. Intention-to-treat analyses were carried out on eligible patients. PFS and OS were estimated by the Kaplan–Meier method and compared by the log-rank test. The hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox proportional hazards model. Subgroup analyses of PFS were compared between the treatment groups using the Cox proportional hazard model. All statistical analyses were conducted using the SAS 9.4 software (SAS Institute Inc., Cary, NC, USA), and a P < 0.05 was considered statistically significant. Forest plot was created using Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA, USA).