Forty-seven patients with squamous cell or small cell lung cancer (28 [60%] of whom had cardiac disease too severe to permit the use of doxorubicin) were treated with cyclophosphamide and VP-16-213 with or without cisplatin. Four of 11 patients with squamous cell (36%) and 19 of 24 patients with small cell (79%) cancers had tumor regressions (eight complete regressions) on the three-drug regimen. Median survival times for the 31 patients with small cell lung cancer were 9 months for those with extensive disease and 12.2 months for those with limited disease. The data suggest that the roles of VP-16-213 and cisplatin need further evaluation in these cell types and that doxorubicin may not be mandatory for successful treatment of squamous cell and small cell lung cancers.