Dealing with initial chemotherapy doses: a new basis for treatment optimisation in limited small-cell lung cancer

Treatment of patients with small-cell lung cancer (SCLC) remains disappointing despite initially high complete response rates. The dramatic initial chemosensitivity of tumor cells is rapidly thwarted by the early emergence of chemoresistant clonogenic cells, regardless of front line treatments. Although a dose-response relationship is well established its effect on survival is inconclusive. From 1980 to 1988, 202 patients with limited SCLC were included in four consecutive trials using an alternating schedule of thoracic radiotherapy and chemotherapy. Despite an increase in chemotherapy and/or the total radiation dose, no significant difference was observed between the four trials in terms of response, disease-free or overall survival. However, a retrospective analysis performed on a total of 131 consecutive patients led us to postulate that a moderate increase in the initial dose, i.e. first course, of cisplatin and cyclophosphamide, could improve overall survival. From 1988 to 1991, 105 consecutive patients were included in a large randomized trial to address this question. The difference in treatment options only concerned the initial doses of cisplatin (80 vs. 100 mg/m2) and cyclophosphamide (900 vs. 1200 mg/m2). According to the triangular test used in this study the trial was closed after inclusion of 105 patients, 32 months after the start of the study because, at that time, overall survival was significantly better in the higher-dose group (p = 0.001). This debatable concept of dose-intensity having an impact on survival offers new possibilities for the management of SCLC. The contribution of hematopoietic support may help to validate this concept.