MAXIMUM-TOLERATED DOSES OF IFOSFAMIDE, CARBOPLATIN, AND ETOPOSIDE GIVEN OVER 6 DAYS FOLLOWED BY AUTOLOGOUS STEM-CELL RESCUE - TOXICITY PROFILE

Purpose: A phase I dose-escalation study of ifosfamide, carboplatin, a nd etoposide (ICE) with autologous stem-cell rescue (ASCR) was conduct ed to determine the maximum-tolerated dose (MTD) of ICE given over 6 d ays. Patients and Methods: One hundred fifty-four patients with a vari ety of poor-prognosis malignancies received escalating doses of ifosfa mide 6,000 to 24,000 mg/m(2), carboplatin 1,200 to 2,100 mg/m(2), and etoposide 1,800 to 3,000 mg/m(2) divided over 6 days. Mesna was admini stered in ct dose equal to ifosfamide. ASCR was performed 48 hours ate r the completion of ICE. The source of stem cells was bone marrow (BM) in patients without BM micrometastases and peripheral-blood stem cell s (PBSC) in patients with BM micrometastases. Patients were evaluated for hematologic and nonhematologic toxicities, as well as response to therapy. Results: The MTD of the ICE regimen is 20,100 mg/m(2) of ifos famide, 1,800 mg/m(2) of carboplatin, and 3,000 mg/m(2) of etoposide. The dose-limiting toxicities of ICE were CNS toxicity and acute renal failure. Additionally, reversible elevations of serum creatinine level s were noted in 29% of patients treated at the upper dose revels. Fort y-six patients were treated at the MTD. Severe, reversible mucositis a nd enteritis were the major nonhematologic toxicities seen at the MTD (78% and 33%, respectively). The overall mortality rate was 8% for all dose levels (4% at the MTD). At the MTD, the median times to an absol ute neutrophil count greater than or equal to 0.5 x 10(9)/L, to a plat elet count greater than or equal to 20 x 10(9)/L, and to discharge wer e 18, 22, and 24 days, respectively. The overall response rate was 40% for 77 patients with assessable disease at the time of treatment. Con clusion: ICE is well tolerated, with acceptable hematopoietic side eff ects and predictable organ toxicity.