S-1 plus cisplatin with concurrent radiotherapy versus cisplatin alone with concurrent radiotherapy for stage III non-small cell lung cancer: a pilot randomized controlled trial

Patient eligibility requirement for enrollment in this study was cytologically or histologically confirmed, unresectable stage IIIA or IIIB NSCLC, diagnosed between January 2009 and November 2011. The clinical or pathologic stage of the disease was determined based on the general rules for the TNM Classification of Malignant Tumors (6th edition) [9]. The other eligibility criteria were an age between 20 and 80 years, Eastern Cooperative Oncology Group performance status of 0 or 1, no previous chemotherapy or radiotherapy, and adequate hematologic, hepatic, and renal function. Patients also had to have the following standard laboratory test results: a leukocyte count of 4000–12 000/μl, a platelet count of ≥100 000/μl, a hemoglobin level of ≥9 g per 100 ml, a serum bilirubin level of ≤1.5 mg per 100 ml, serum aspartate aminotransferase and alanine aminotransferase levels of ≤100 IU/ml, an alkaline phosphatase level of no more than twice the upper limit of normal, a normal creatinine level, and a partial pressure of arterial oxygen of ≥65 torr in room air. All eligible patients underwent computed tomography (CT) scans of the thorax, including the upper abdomen, and a radioisotopic bone scan.

Patients who were pregnant or who had malignant pleural effusion, malignant pericardial effusion, a concomitant malignancy, or serious comorbidities such as clinically significant cardiac dysfunction, active infection, or neurologic or psychiatric disorders were excluded from the study. The study was approved by the institutional ethics committee of Third Affiliated Hospital of Harbin Medical University with permission number (KY2009-41).

The randomization code was generated using a computerized number generator through the stratified block randomization method of the SAS package (Version 9.1.3; SAS Institute Inc., Cary, North Carolina, USA) by a statistician with no clinical involvement in this study. After qualifying, patients were assigned to either of two treatment groups: SCCR group or CCR group. The allocation was concealed in sequentially numbered, opaque, sealed envelopes containing the randomization assignments. In addition, all the outcome assessors and data analysts were blinded in this study.

A CT scan of the chest tumor was conducted in order to determine tumor volume before therapy. Patients in the CCR group received cisplatin (60 mg/m²) on day 1 and then at 4-week intervals, and they also underwent radiotherapy, which was administrated concurrently on day 1 by chest irradiation. Two different radiation target volumes were planned. The initial dose (approximately 40 Gy) was administered to the primary tumor, the ipsilateral hilum with a 2-cm margin, and the involved mediastinal lymph nodes with a 1-cm margin. Prophylactic radiation fields were not planned, except for subcarinal lymph nodes. Subsequently, a 20 Gy dose was given as a booster once a day for 5 days each week over a period of 6 weeks using a linear accelerator generating at least 4 MeV photons, in accordance with tumor shrinkage. In addition to receiving the same intervention as the CCR group, patients in the SCCR group were also administered S-1 (orally at 40 mg/m² per dose, b.i.d., on days 1 through 14).

All eligible patients who received treatment were considered assessable for response and toxicity measures. Chest radiography, complete blood counts, and blood chemistry measurements were performed weekly during the treatment period. The response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) [10]. The toxicity for all patients who received any treatment was evaluated and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 [11].

An intention to treat analysis was performed. Progression-free survival (PFS) was defined as the time from the starting date of induction chemoradiotherapy until disease progression or death. Patients whose disease had not progressed at the time of study treatment discontinuation continued to be assessed until progression was documented. Overall survival (OS) was defined as the time from the starting date of induction chemoradiotherapy until death from any cause. Sample size was calculated on the basis of an expected 15% difference between the 2 groups. OS was calculated from the day of randomization to the day of death. Data for surviving patients were censored on the date on which they were last known to be alive. PFS was computed from the date of randomization to the date of relapse, death, or completion of follow-up, whichever occurred first. Data on patients who were alive and progression free were censored at the time of the last follow-up visit. OS and PFS rates were calculated using the Kaplan–Meier method, and P ≤ 0.05 was considered statistically significant. All P values were obtained using 2-tailed t-tests.