STUDY OF DOSE-ESCALATION OF TENIPOSIDE (VM-26) PLUS CISPLATIN (CDDP) WITH RECOMBINANT HUMAN GRANULOCYTE-COLONY-STIMULATING FACTOR (RHG-CSF) IN PATIENTS WITH ADVANCED SMALL-CELL LUNG-CANCER

A dose escalation study of teniposide (VM-26) plus cisplatin (CDDP) was carried out using recombinant human granulocyte colony-stimulating factor (rhG-CSF) in 46 previously untreated patients with advanced small cell lung cancer (SCLC). The dose of CHOP was 80 mg/m(2)/day intravenously (i.v.) (day 1) and VM-26 was escalated from 60 mg/m(2)/day to 80, 100 and 120 mg/m(2)/day i.v. x 5 days for four cycles. The dose of rhG-CSF was 90 mu g/m(2)/day subcutaneously for 13 days. The feasibility of the regimen at the starting dose level of VM-26 with or without rhG-CSF was initially examined in 10 patients chosen through random allocation. WHO grade 4 neutropenia was observed in 17% (three out of 18 courses) of patients in the rhG-CSF group and in 63% (12 out of 19 courses) of the control group (P < 0.01). The number of patients with febrile episodes (> 38 degrees C) over the four courses of chemotherapy was 1 in the rhG-CSF group and 4 in the control group. According to these results, all 36 patients received rhG-CSF in the dose escalation stage. The incidence of WHO grade 4 neutropenia at the dose levels of 60, 80, 100 and 120 mg/m(2)/day of VM-26 was 66, 57, 76 and 85%, respectively (P > 0.1). The incidence of grade 4 thrombocytopenia was 19, 31, 18 and 46%, respectively (P > 0.1). The overall response rate was 100% in patients with Limited stage SCLC and 83% in patients with extensive stage SCLC. The actual administered VM-26 dose per week at the dose level of 100 mg/m(2)/day was 1.6-fold higher than the planned starting dose (60 mg/m(2)/day) per week. At the dose level of 120 mg/m(2)/day, 50% of patients developed WHO grade 4 leucopenia, which lasted longer than 1 week and 67% of the patients had WHO grade 3 or 4 diarrhoea. At this same dose, all patients had at least one febrile episode (> 38 degrees C), and 1 patient died of cerebral bleeding with severe thrombocytopenia. The median survival time of all patients was 451 days (411 days, extensive disease; 497 days, limited disease). VM-26 plus CDDP with rhG-CSF was active in previously untreated patients with SCLC. The recommended dose of VM-26 in combination with CDDP for a phase II study is 100 mg/m(2)/day for 5 days with rhG-CSF support.