In three German multicenter randomized trials, which included 718 patients, the activity of ifosfamide in small cell lung cancer (SCLC) was tested. In study 1, IE (ifosfamide, 1.5 g/m2, days 1 through 5; etoposide, 120 mg/m2, days 3 through 5) alternating with CAV (cyclophosphamide, 600 mg/m2, days 1 and 2; doxorubicin, 50 mg/m2, day 1; vincristine, 2 mg, day 1) was compared with a response-oriented treatment with IE therapy up to maximum response and subsequently an immediate switch to CAV. After chemotherapy, patients with limited disease received chest irradiation with 45 Gy. Prophylactic cranial irradiation (30 Gy) was given to all patients who achieved complete response (CR). A total of 324 patients were evaluable. Total response rate (CR + partial response [PR]) was 75% v 78% for the two treatment groups; the CR rate was 29% for both groups. Survival was nearly identical in both arms, with a median survival of 10.0 months for all patients, 12.0 months for those with limited disease (LD), and 7.5 months for those with extensive disease (ED). The 2-year survival rate was 11%. In study 2, IE was compared with PE (cisplatin, 90 mg/m2, day 1; etoposide, 150 mg/m2, days 3 through 5). A total of 141 patients were evaluable. Total response (CR + PR) rate was 65% for PE and 68% for IE; the CR rate for PE was 32% v 20% for IE. Survival favored PE with a median survival of 11.6 months v 9.4 months for all patients, 14.8 months v 11.0 months for LD, and 8.9 months v 7.5 months for ED. Two-year survival rates were 12% v 9% for all patients, 23% v 10% for those with LD, and 5% v 9% for those with ED. From these trials, we conclude that IE is an active and well-tolerated regimen for SCLC, and that PE may be superior to IE in limited-stage disease. Taking these results into account, we modified our chemotherapy protocols in study 3 and compared IAV (ifosfamide, 2 g/m2, days 1 to 5; doxorubicin, 25 mg/m2, days 1 and 2; vincristine, 2 mg, day 1) alternating with either PE or JE (carboplatin, 300 mg/m2, day 1; etoposide, 120 mg/m2, days 1 to 3). Interim results of 253 evaluable patients are as follows: CR + PR rate after 4 cycles was 68%; the CR rate was 28%; median survival was 11.6 months for all patients, 14.8 months for LD, and 10.2 months for ED.(ABSTRACT TRUNCATED AT 400 WORDS)