Dose-intensive therapy in small cell lung cancer

Basic to curative treatment for small cell lung cancer (SCLC) are the principles of dose response, combination chemotherapy, and combined-modality therapy. Theory and experimental and clinical data suggest that solid tumors recur, despite initially responding to chemotherapy due to drug resistance. Resistance to chemotherapy is potentially overcome by using 5- to 10-fold higher doses. To decrease the emergence of drug resistance, combinations of active non-cross-resistant agents are used. Hematopoietic stem cell support provides the opportunity to test dose response to the limits of organ tolerance. Dose-intensive therapy for lung cancer patients is complicated by the fact that this disease most often occurs in an older-aged population (median, 60 to 65 years) with underlying smoking-related comorbid disease, early metastatic spread, and enhanced risk of secondary smoking-related malignancies. In a phase II feasibility trial just activated, patients younger than 60 years of age with limited-stage SCLC are being treated with four cycles of cisplatin and etoposide and concurrent twice-daily chest radiotherapy to 45 Gy (150-cGy fractions). Those patients achieving complete or near-complete response will receive high-dose cyclophosphamide/cisplatin/ carmustine with autologous stem cell support. Upon recovery, prophylactic cranial irradiation will be given. Results could lead to a phase III trial testing the concept of dose intensification. This article reviews evidence for the contribution of dose intensification to response and survival in the treatment of SCLC, the adequacy of the clinical trial's design to address these relationships, and suggestions for future directions. The strategies of dose-intensive induction therapy, multicycle dose-intensive combination therapies, chest radiography, and stem cell purging trials will be discussed.