title: 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.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  umin.ac.jp/ctr Identifier: C000000221.
authors.affiliation: Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, Morioka.
authors.forename: T
authors.initials: T
authors.lastname: Sugiyama
authors.forename: K
authors.initials: K
authors.lastname: Fujiwara
authors.forename: Y
authors.initials: Y
authors.lastname: Ohashi
authors.forename: H
authors.initials: H
authors.lastname: Yokota
authors.forename: M
authors.initials: M
authors.lastname: Hatae
authors.forename: T
authors.initials: T
authors.lastname: Ohno
authors.forename: Y
authors.initials: Y
authors.lastname: Nagai
authors.forename: N
authors.initials: N
authors.lastname: Mitsuhashi
authors.forename: K
authors.initials: K
authors.lastname: Ochiai
authors.forename: K
authors.initials: K
authors.lastname: Noda
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D059248:Chemoradiotherapy; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008055:Lipids / Q000627:therapeutic use*; D008351:Mannans / Q000627:therapeutic use*; D008875:Middle Aged; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D002583:Uterine Cervical Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*
chemical_list: D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D008055:Lipids; D008351:Mannans; C031208:specific substance maruyama
keywords: Z-100; cervical cancer of the uterus; chemoradiotherapy; dose of immunomodulator; immunotherapy; radiotherapy