One hundred eight eligible patients with advanced, metastatic non-small-cell lung cancer (NSCLC) were randomized to treatment with either cyclophosphamide, doxorubicin, and cisplatin (CAP) followed by mitomycin, lomustine, and methotrexate (MCM) on progression (sequential, 54 patients) or to CAP alternating with MCM (alternating, 54 patients). The regression rate (30%) was identical for both treatments. In addition, there were no statistically significant differences noted between treatments for regression duration (6.9 months v 7.6 months), time to progression (2.1 months v 4.4 months), or overall survival (5.5 months v 6.9 months). The lack of advantage for the theoretically superior alternating approach was probably due to a combination of relative ineffectiveness of each treatment and lack of complete non-cross resistance.