Our purpose was to determine the ability of an etoposide-cisplatin (EP )-based regimen to salvage patients with limited and extensive small-cell lung cancer who are incomplete responders to cyclophosphamide-Adriamycin-vincristine-etoposide (CAVE) chemotherapy, and to determine the ability of thoracic radiation therapy (TRT) to salvage CAVE and EP incomplete responders. Fifty-eight patients with small-cell lung cancer (33, limited disease; 25, extensive disease) were entered on this Phase II study between November 1984 and December 1987. Patients received three cycles of CAVE chemotherapy, followed by two cycles of CEPi (cyclophosphamide-etoposide-cisplatin (infusional) and two cycles of CE (cyclophosphamide-etoposide) in conjunction with TRT and prophylactic cranial irradiation (PCI). The overall response rate to CAVE was 62% [5% complete response (CR), 57% partial response (PR) + regression (REGR)]. Of the patients who failed to achieve a CR with CAVE, 81% responded to CEPi (44% CR, 36% PR). Of the patients who did not achieve a CR with either CAVE or CEPi, 89% responded to TRT (65% CR, 24% PR + REGR). For the 33 patients with limited disease, the median survival time and 2-year survival rate were 16.1 months and 24%, respectively. The corresponding figures for the 25 patients with extensive disease were 9.8 months and 4%, respectively. Eleven of these 25 patients were "downstaged" to "limited disease" with CAVE + CEPi and then received TRT + PCI + CE. Their median survival time and 2-year survival rate were 12.6 months and 9%, respectively. The EP-based regimen CEPi and TRT were able to convert 44 to 65% of patients to a complete response who had failed to do so with non-EP induction chemotherapy. This study supports the use of an EP regimen with TRT as initial therapy for newly diagnosed small-cell lung cancer.