DOUBLE-CONDITIONING REGIMENS CONSISTING OF THIOTEPA, MELPHALAN AND BUSULFAN WITH STEM-CELL RESCUE FOR THE TREATMENT OF PEDIATRIC SOLID TUMORS

Major dose-limiting factors of high-dose thiotepa (TEPA) and melphalan are life-threatening mucositis and neurotoxicity, To administer a max imum dose of these drugs safely and to obtain a maximum anti-cancer ef fect, a double-conditioning regimen with a single grafting, two cycles of administration of a combination of TEPA (300-600 mg/m(2)) plus mel phalan (70-150 mg/m2) with a 1-week interval was attempted in 20 patie nts with pediatric advanced or chemotherapy-resistant solid tumors (se ven rhabdomyosarcoma, four hepatoblastoma, three neuroblastoma and fou r other malignancy). Combinations of TEPA plus melphalan/busulfan (Bu) (8-10 mg/kg) and TEPA plus Bu were given to four and two patients wit h brain tumors, respectively, In an additional two patients, three cyc les of drug administration were performed, According to the results of the dose-escalating study, the maximum tolerable doses of TEPA and me lphalan for children aged 2 years old or older were 1000 mg/m(2) and 2 80 mg/m(2), respectively. Mucositis was dose-limiting, Renal toxicity was also dose-limiting in young children (<2 years old), There were tw o treatment-related deaths (7%) (fungal pneumonia and renal tubular ac idosis), Among 13 patients who received high-dose chemotherapy during CR, 10 are alive with no evidence of disease (15-59 months, median: 35 months) and in 13 evaluable patients without CP, six are alive withou t regrowth of the disease (14-59 months, median: 39 months), Thus, the se novel conditioning regimens allowed us to increase the dose intensi ty to nearly the maximum for each drug and seemed to reduce adverse ef fects compared to previously reported regimens with these drugs, With regard to the effect on outcome, the results of this study seem to be encouraging, but a further study on a larger number of patients is req uired.