Noda K et al. (2006) 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. Gynecol Oncol 101: 455–463

Radiotherapy alone has limited efficacy in treating patients with advanced cervical cancer; however, radiotherapy might be enhanced by concomitant administration of immunotherapeutic agents. Previous findings indicate that the immunomodulatory drug Z-100 (Zeria Pharmaceutical Co., Ltd, Tokyo, Japan) is most effective as an adjunctive therapy when used at high doses, but a randomized phase III trial by Noda et al. suggests otherwise.

Between June 1995 and March 1999, 221 patients with locally advanced cervical cancer were enrolled in the study; follow-up continued until September 2002. Patients were randomized to low-dose (0.2 µg/2 ml/ampoule; n = 109) or high-dose (40 µg/2 ml/ampoule; n = 108) Z-100, administered subcutaneously twice weekly, in combination with radiotherapy (50–55 Gy). The response rate was not significantly different between the two groups. Five-year survival was significantly better in the low-dose than in the high-dose group (58.2% vs 41.5%; P = 0.039), with the largest difference observed in patients with a higher parametrial invasion. Progression-free survival was also significantly improved in patients receiving the low-dose Z-100 (P = 0.048). Survival in the higher-dose group was similar to that in previous studies with radiotherapy alone.

The authors conclude that, when used over a long period, Z-100 improves survival at low doses, but that this survival advantage is lost when the drug is administered at higher doses. They highlight the need for determining optimum doses of immunomodulators and other agents for maximum survival benefit, using placebo controls and high and low doses; a further placebo-controlled, randomized trial is therefore underway.