Multimodality treatment including early high-dose chemotherapy with peripheral blood stem cell transplantation in limited-disease small cell lung cancer.

Combined-modality treatment for limited-disease small cell lung cancer using conventional chemotherapy and chest irradiation achieves high response rates, but most patients relapse over a period of 12 to 16 months. To improve current results, we performed a phase II trial including high-dose chemotherapy and peripheral blood progenitor cell transplantation (PBPCT) as part of an early intensification strategy after two cycles of induction therapy. Moreover, to reduce the risk of local recurrence, the protocol included surgical resection in stages I to IIIA patients as well as chest irradiation. Between January 1991 and July 1994, 16 consecutive patients (median age, 50 years; age range, 30 to 59 years) were treated in this single-center trial. The patients received two cycles of conventional chemotherapy consisting of etoposide 500 mg/m2, ifosfamide 4 g/m2, cisplatin 50 mg/m2, and epirubicin 50 mg/m2 plus granulocyte colony-stimulating factor 5 microg/kg at a 3-week interval, followed by PBPC collection and subsequent high-dose etoposide 1,500 mg/m2, ifosfamide 12 g/m2, carboplatin 750 mg/m2, and epirubicin 150 mg/m2 with PBPCT. The duration of the entire chemotherapy program was 9 weeks. Six of 10 patients in stages I to IIIA and one of six patients in stage IIIB received neoadjuvant or adjuvant surgery before high-dose chemotherapy, followed by thoracic (50 Gy) and prophylactic (30 Gy) cranial irradiation. Hematopoietic reconstitution after high-dose chemotherapy occurred within 11 days (range, 9 to 17 days) for both neutrophils (>0.5 x 10(9)/L) and platelets (>20 x 10(9)/L). Oral mucositis (World Health Organization grade 2 to 4) was the predominant nonhematologic toxicity, which was observed in 12 of 16 patients. One patient developed neutropenic septicemia with fatal multiorgan failure. At a median follow-up of 44 months (range, 32 to 77 months) after PBPCT, nine patients are alive and well, resulting in a disease-free and overall survival rate of 56.3% +/- 12.4%. The median overall survival has not yet been achieved. None of the patients who had surgery relapsed or died after therapy. All relapses occurred within the first 12 months after PBPCT. Patients in stages I to IIIA (10 patients) had a 70% +/- 14% overall survival rate at 4 years, while patients in stage IIIB (six patients) had a 33% +/- 19% survival rate at 4 years, with a median survival of 17 months posttransplant. These data demonstrate that a multimodality treatment including early high-dose chemotherapy with PBPCT may lead to a prolonged disease-free survival in the majority of patients. A randomized phase III study has now been initiated to prospectively investigate the role of high-dose chemotherapy, surgery, and chest irradiation in the multidisciplinary approach to limited-disease small cell lung cancer.