For two chemotherapy regimens to be truly non-cross-resistant, each should be active as first-line therapy and also as second-line therapy. The effectiveness of both cyclophosphamide, doxorubicin, and vincristine (CAV) and etoposide and cisplatin (VPP) in previously untreated patients with small cell lung cancer has been well-documented. Also, VPP has caused tumor regression in up to 50% of patients when used as second-line therapy after CAV. The effectiveness of CAV after progression or relapse after VPP has not been documented. We identified 29 patients who received CAV after their tumors failed to respond or relapsed after VPP or etoposide and carboplatin (VPC). There were 21 male and eight female patients (median age, 57 years; range, 30-79). Thirteen patients were treated following failure to respond to VPP or VPC and 16 at the time of relapse. Eight patients had limited disease and 21 had extensive disease. Metastatic sites included liver (11 patients), bone (ten), lymph nodes (seven), bone marrow (three), brain (four), and contralateral lung (one). There were three complete responses (durations of 16, 22, and 26 weeks) and five partial responses (duration, 8+ to 36 weeks). Three patients had stable disease and 18 patients had disease progression while receiving treatment. The median survival of the entire group was 15 weeks. Responding patients had a median survival of 34 weeks (range, 8+ to 72+) and stable and nonresponding patients had a survival of only 9 weeks (range, 2-38). A granulocyte count nadir less than 500 X 10(9)/L was seen after 7.9% of evaluable treatment cycles and a platelet count nadir less than 50,000 X 10(9)/L occurred after only 5.3% of cycles. Five patients required transfusion for anemia, and two patients required dose reduction of vincristine for peripheral neuropathy. This study demonstrates that CAV has limited activity following failure to respond to VPP.