Phase III double-blind randomized trial of radiation therapy for stage IIIb cervical cancer in combination with low- or high-dose Z-100: Treatment with immunomodulator, more is not better

Background.To evaluate the efficacy of low or high-dose immunomodulator, Z-100, in combination with radiotherapy for cervical cancer.Methods.Between 1995 and 1999, 221 patients with stage IIIb squamous cell carcinoma of the cervix were randomly assigned to treatment with Z-100 either at 0.2 μg or 40 μg in a double-blind manner in combination with radiotherapy.Results.The 5-year survival of patients with high-dose and low-dose Z-100 was 41.5% (95% CI: 31.7–51.3%) and 58.2% (95% CI: 48.7–67.7%), respectively, showing a 30% reduction in the death rate (hazard ratio: 0.670 [95% CI: 0.458–0.980], P = 0.039). Survival of high-dose group was equivalent to the 4-year survival of the radiotherapy plus hydroxyurea arm (49.7%) of GOG120 study, and that of low-dose group was similar to the survival of the cisplatin-based chemoradiation arm. The progression-free survival was also significantly improved in favor of low-dose group (hazard ratio: 0.667 [95% CI: 0.447–0.997], P = 0.048). The survival of low-dose group was similar to the survival of the cisplatin-based chemoradiation arms of the GOG120 study.Conclusions.Unexpectedly, the survival of patients with advanced cervical cancer treated by lower dose of Z-100 in combination with radiotherapy was significantly better than those treated with higher dose Z-100, which was equivalent to the survival with radiotherapy alone. The hypothesis that lower dose of Z-100 enhances the efficacy of radiation therapy is now being tested by placebo-controlled randomized trial.