Cisplatin, ifosfamide, and prolonged oral etoposide in the treatment of patients with extensive small cell lung carcinoma

The combination of cisplatin, ifosfamide, and prolonged oral etoposide (PIE) was studied in patients with extensive small cell lung carcinoma (SCLC) in a Phase I trial followed by a Phase II trial to determine the maximum tolerated dose (MTD), characterize toxicity, and estimate response and median survival rates.Thirty-three patients were treated between October 1991 and December 1994. Doses for the initial cohort were cisplatin 20 mg/m2/day, ifosfamide 1500 mg/m2/day with mesna (all given intravenously on Days 1-3), and oral etoposide 50 mg/m2 on Days 4-17. This cycle was repeated every 4 weeks for up to 6 cycles. The MTD was reached for the first 9 patients. For these 9 patients and the next 24 patients, who were entered in the Phase II trial, response and survival were estimated.Dose-limiting toxicity was manifested as Grade 4 neutropenia in 3 of 3 patients (associated with fever in 2 of 3), and Grade 4 thrombocytopenia was encountered in 2 of 3 patients at the second dose level. Of 6 patients treated at the first dose level, 4 achieved targeted myelosuppression (absolute granulocyte count nadir1000), but only 1 experienced Grade 4 neutropenia, defining this level as the MTD. Grade 4 neutropenia and/or thrombocytopenia was observed in 36 (24%) of a total of 152 courses administered at or below the MTD. Nonhematologic toxicity above Grade 2 was uncommon, excluding nausea and vomiting. Overall objective response rate was 93% of 30 evaluable patients: 5 (17%) complete responses and 23 partial responses (76%). Median failure free and overall survival durations were 36 and 54 weeks, respectively.The combination of cisplatin, ifosfamide, and oral etoposide produced encouraging failure free and overall median survival rates in patients with extensive SCLC. These results warrant further evaluation of this regimen in the initial therapy of patients with limited stage disease.