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

• Published in: Gynecologic oncology 2006-06, Vol.101 (3), p.455-463
• Main Authors: Noda, Kiichiro, Ohashi, Yasuo, Sugimori, Hajime, Ozaki, Masami, Niibe, Hideo, Ogita, Sachio, Kohno, Ichiro, Hasegawa, Kazuo, Kikuchi, Yuzo, Takegawa, Yoshihiro, Fujii, Shingo, Tanaka, Kenichi, Ochiai, Kazunori, Kita, Midori, Fujiwara, Keiichi
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - adverse effects; Adjuvants, Immunologic - therapeutic use; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - pathology; Carcinoma, Squamous Cell - radiotherapy; Cervical cancer; Combined Modality Therapy; Disease-Free Survival; Dose-Response Relationship, Immunologic; Double-Blind Method; Female; Humans; Immunomodulator; Lipids - adverse effects; Lipids - therapeutic use; Mannans - adverse effects; Mannans - therapeutic use; Middle Aged; Neoplasm Staging; Radiotherapy; SSM; Uterine Cervical Neoplasms - drug therapy; Uterine Cervical Neoplasms - pathology; Uterine Cervical Neoplasms - radiotherapy; Z-100
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2005.11.006

To evaluate the efficacy of low or high-dose immunomodulator, Z-100, in combination with radiotherapy for cervical cancer. 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. 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. 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.