Significant advances have been made in the treatment of small cell lung cancer (SCLC) during the past two decades. Major and indisputable improvement has been achieved in patients with limited disease. However, progress in extensive SCLC has been more elusive. Despite thousands of patients entered into numerous phase II and phase III studies, it is still debatable whether any particular regimen is superior to older combination chemotherapy regimens first studied 20 years ago. From May 1989 through January 1993, 171 patients with extensive SCLC were entered into a Hoosier Oncology Group phase III study comparing etoposide/cisplatin (VP) with etoposide/ifosfamide/cisplatin (VIP). There were 166 patients fully evaluable for response and survival. As expected, hematologic toxicity was more severe in the patients in the VIP arm, but both arms had a 6% to 7% treatment-related mortality rate. The response rate were similar (70% v 66%, with 18% and 21% complete remissions). However, there was improved survival in the VIP arm (P = .03). This was most pronounced at the tail of the survival curves, with 2- and 3-year survival rates of 12% and 5% for VIP compared with 5% and 0% for VP. A different form of VIP chemotherapy for patients with refractory SCLC with no prior ifosfamide also was evaluated. From February 1990 to August 1993, 46 patients with previously treated SCLC were treated with daily oral etoposide/ifosfamide/cisplatin. Thirty-one of 41 evaluable patients had prior cisplatin plus intravenous etoposide. Myelosuppression was significant, with six treatment-related deaths. Twenty-two of 41 patients (54%) had an objective response, including six (15%) complete remissions. The median length of survival was 29 weeks (range, 1 to 76 weeks). Despite the toxicity, these results are competitive with many first-line chemotherapy programs. This is a reasonable, aggressive regimen for selected patients with refractory SCLC.