Pilot study of topotecan and high-dose cyclophosphamide for resistant pediatric solid tumors

Background. The recommended dosages of topotecan and cyclophosphamide in co mbination for prior-treated patients - 3.75 mg/m(2) and 1,250 mg/m(2) in ch ildren, 5 mg/m(2) and 600 mg/m(2) in adults, respectively - are well below those of each agent when used singly. We tested the hypothesis that much hi gher dosing would meet critical goals of salvage therapy: antitumor effect and a lark of toxicity to key organs, so as not to preclude subsequent cons olidative treatments needed for cure. Procedure, Patients with resistant pe diatric solid tumors received cyclophosphamide 4,200 mg/m(2) by 48 hr infus ion, and topotecan 6 mg/m(2) by 72 hr infusion (HD-Cy/Topo). Mesna and gran ulocyte colony-stimulating factor were used. Cycles were repeated when neut rophil counts were >1,000/ul and platelet counts were >75,000/uL. Results, Twenty-eight patients, aged 2 to 33 years (median, 14), received one (n = 4 ), two (n = 15), or greater than or equal to3 (n = 9) cycles of HD-Cy/Topo. All patients had previously received greater than or equal to6 cycles of o ther therapy, high-dose alkylator-based chemotherapy, and/or etoposide- and doxorubicin-containing regimens. HD-Cy/Topo was given in an outpatient set ting. Profound myelosuppression was the major toxicity, but retreatment was possible by day 28, and preliminary results with peripheral blood stem cel l collections showed a sparing effect on hemopoietic stem cells. Mucositis was uncommon. After HD-Cy/Topo, cardiac;renal, hepatic, and pulmonary funct ion remained within the normal range. Partial or minor responses were noted in neuroblastoma, desmoplastic small round-cell tumor, Ewing sarcoma, rhab domyosarcoma, and osteosarcoma. Conclusions. its antitumor potential and li mited toxicity make HD-Cy/Topo an attractive choice for inclusion in aggres sive salvage programs aimed at achieving cures of resistant tumors. it may also merit incorporation into frontline treatment protocols. (C) 2000 Wiley -Liss, Inc.