This was an open-label, single-center, randomized, parallel phase II study (ClinicalTrials.gov NCT00816634). The protocol was reviewed and approved by the institutional review board at Samsung Medical Center ((#200807059, Seoul, Korea) and the trial was conducted in accordance with the Declaration of Helsinki. Patients with recurrent or metastatic squamous cell carcinoma of the esophagus who had not previously been treated palliative chemotherapy for metastatic disease were eligible. Patients were required to have at least one measurable metastatic lesion as defined by the Response Criteria in Solid Tumors (RECIST) v1.0, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, a life expectancy of at least 3 months, and adequate hematologic (neutrophil count ≥ 1500/mm3, platelet count ≥ 100,000/mm3, hemoglobin ≥ 9.0 g/dl), renal (serum creatinine ≤ 1.5 mg/dl or creatinine clearance ≥ 50 ml/min) and liver function (bilirubin ≤ 1.5 mg/dl, AST/ALT ≤ 3 times the upper normal limit). Patients with no prior chemotherapy or only adjuvant chemotherapy that had been completed more than 6 months before registration, and no radiotherapy within 4 weeks before study registration were eligible. Patients who had other types of esophageal cancer tumors, central nervous system metastasis, severe comorbid illness, or active infection, and women who were pregnant or lactating, were excluded from the study. The nature of the study was fully discussed with the patients before the initiation of treatment, including an explanation of the risks and possible discomfort, as well as the potential benefits, and written informed consent was obtained.
Eligible patients were stratified by their ECOG performance status (0–1 vs. 2), and randomly assigned to receive CC (capecitabine 1000 mg/m2 orally twice a day on days 1–14 plus 75 mg/m2 of cisplatin intravenously on day 1) or CP (capecitabine as for CC plus 80 mg/m2 of paclitaxel intravenously on days 1 and 8). An identical dose regimen of capecitabine was used for both treatment arms. Study treatment was repeated every 3 weeks until documented disease progression, unacceptable toxicity, or patient refusal. Supportive care, including adequate pre- and post-hydration for patients in the CC arm and corticosteroids for patients in the CP arm, was provided according to guidelines. The use of hematopoietic growth factors was not allowed during treatment, except for patients with febrile neutropenia or grade 4 myelosuppression at the investigators’ discretion. Each cycle of chemotherapy was given if the patient’s blood counts had returned to normal and non-hematologic toxicities had resolved. All patients received chemotherapy as outpatients. After combination chemotherapy failed, second-line chemotherapy was recommended to all patients if their performance status was preserved.
The dosage of subsequent cycles was adjusted according to the toxic effects that developed during the preceding cycle. Baseline evaluation included a complete medical history and physical examination, blood counts, serum chemistry, chest x-ray, and chest computed tomography (CT) scan. Follow-up history, physical examination and toxicity assessment were performed before each 3-week cycle of treatment. Toxicity grading was based on the National Cancer Institute criteria (NCI-CTCAE version 3). The first evaluation with imaging was performed 6 weeks after the start of study treatment. Response was evaluated according to the RECIST criteria and was assessed by chest CT or by the same tests that were initially used to stage the tumor. In case of complete radiologic response, endoscopic evaluation of the primary tumor, if present, was mandatory. Progression in non-measurable lesions that led to deterioration of patient status was classified as progressive disease regardless of the status of the measurable lesions. We also assessed quality of life (QOL) using the EORTC-QLQ-OES18, which contains four scales that address dysphagia, eating difficulties, reflux, and esophageal pain, and six single items for problems with coughing, dry mouth, taste, choking when swallowing, speech, and swallowing saliva. These self-administered questionnaires were completed by patients at baseline, every two cycles, and at the end of treatment. QOL scores were descriptively recorded as baseline values and changes from baseline. As a general criterion for clinically significant improvement or deterioration, we defined a difference of ten or greater from baseline mean score as a clinically significant change.
The primary objective of this study was to assess the response rate in both treatment arms. Secondary objectives included assessment of PFS, OS, toxicity and QOL. This randomized phase II trial was statistically treated as two simultaneous phase II studies and the Simon’s two-stage optimal design was applied separately for each treatment arm [13]. A sample size of 94 patients was required to accept the hypothesis that the true response rate in each arm was greater than 40 % with 80 % power, and to reject the hypothesis that the response rate was less than 20 % with 5 % significance. In the first stage, if there were fewer than four responses out of the initial 13 patients for each group, early termination of the study was required. PFS and OS were estimated according to the Kaplan-Meier method, and the changes in QOL scores were calculated with a paired t-test. Since the study was designed to assess chemotherapy outcomes for two regimens simultaneously, exploratory analyses of efficacy were carried out using the Cox regression model. All data were analyzed using R for Windows software (version 2.11.1, http://www.r-project.org).
