Phase III placebo-controlled double-blind randomized trial of radiotherapy for stage IIB-IVA cervical cancer with or without immunomodulator Z-100: a JGOG study.

BACKGROUND: Based on the result of our previous study showing better overall survival (OS) at the lower dose (0.2 µg) of immunomodulator Z-100 than higher dose (40 µg) in patients with locally advanced cervical cancer who received radiotherapy, we conducted a placebo-controlled double-blind randomized trial. PATIENTS AND METHODS: Patients of stages IIB-IVA squamous cell carcinoma of the uterine cervix were randomly assigned to receive Z-100 at 0.2 µg (Z) or placebo (P). The study agent was given subcutaneously twice a week during the radiotherapy, followed by maintenance therapy by administering once every 2 weeks until disease progression. Primary end point was OS, and secondary end points were recurrence-free survival, and toxicity. RESULTS: A total of 249 patients were randomized. Death events occurred extremely slower than expected, and Independent Data Monitoring Committee recommended to analyze the survival result prematurely. The 5-year OS rate was 75.7% [95% confidence interval (CI) 66.4% to 82.8%] for Arm Z and 65.8% (95% CI 56.2% to 73.8%) for Arm P (P = 0.07); hazard ratio was 0.65 (95% CI 0.40-1.04). Survival benefit in Arm Z was observed regardless of chemoradiation or radiation alone. There was no trend in recurrence-free survival between the two arms. Side-effects were not different between two arms. CONCLUSION: Z-100 showed a trend of improvement on OS in locally advanced cervical cancer, although the statistical power was less than anticipated because survival rates were unexpectedly higher than expected for both arms. Validation of potential survival benefit of immune modulation should be made. TRIAL REGISTRATION: umin.ac.jp/ctr Identifier: C000000221.