High-dose carboplatin, etoposide and cyclophosphamide with autologous bone marrow transplantation for the treatment of advanced malignancies: a phase I study

Abstract

Carboplatin is a platinum-derivative widely used in conditioning regimens with ABMT, particularly in combination with cyclophosphamide and etoposide, drugs which co-express synergism in vitro. The objective of this study was to determine the maximum tolerated dose (MTD) of this combination. Thirty-four patients with refractory lymphoid or solid tumors were treated in a dose-escalation study with continuous infusion carboplatin (1.2-2 g/m2) on days -7 to -4, etoposide (1.2-2.4 g/m2) on days -7 to -5 and cyclophosphamide (120 mg/kg) given in two dose schedules: (1) day -3, -2; (2) day -9, -8. Autologous bone marrow or peripheral blood stem cells were infused on day 0. Mucositis/enterocolitis was dose limiting. In addition, severe cardiac dysfunction occurred in schedule 1 but not in schedule 2. Renal dysfunction occurred in the setting of fungemia, respiratory failure and congestive heart failure, and did not correlate with carboplatin dose. Hepatic and pulmonary dysfunction were minimal. The MTD was etoposide 2.1 g/m2 and carboplatin 2.0 g/m2, in combination with cyclophosphamide (120 mg/kg) on schedule 2. Responses were seen in 16 of 19 patients with measurable disease. Seven patients are disease-free survivors 50-60+ months post-ABMT. This study defines the MTD of carboplatin when combined with etoposide and cyclophosphamide in patients with adequate renal function and suggests significant anti-tumor activity.