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

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Abstract
Background The recommended dosages of topotecan and cyclophosphamide in combination for prior‐treated patients—3.75 mg/m2 and 1,250 mg/m2 in children, 5 mg/m2 and 600 mg/m2 in adults, respectively—are well below those of each agent when used singly. We tested the hypothesis that much higher dosing would meet critical goals of salvage therapy: antitumor effect and a lack of toxicity to key organs, so as not to preclude subsequent consolidative treatments needed for cure. Procedure Patients with resistant pediatric solid tumors received cyclophosphamide 4,200 mg/m2 by 48 hr infusion, and topotecan 6 mg/m2 by 72 hr infusion (HD‐Cy/Topo). Mesna and granulocyte colony‐stimulating factor were used. Cycles were repeated when neutrophil 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 ≥3 (n = 9) cycles of HD‐Cy/Topo. All patients had previously received ≥6 cycles of other therapy, high‐dose alkylator‐based chemotherapy, and/or etoposide‐ and doxorubicin‐containing regimens. HD‐Cy/Topo was given in an outpatient setting. Profound myelosuppression was the major toxicity, but retreatment was possible by day 28, and preliminary results with peripheral blood stem cell collections showed a sparing effect on hemopoietic stem cells. Mucositis was uncommon. After HD‐Cy/Topo, cardiac, renal, hepatic, and pulmonary function remained within the normal range. Partial or minor responses were noted in neuroblastoma, desmoplastic small round‐cell tumor, Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma. Conclusions Its antitumor potential and limited toxicity make HD‐Cy/Topo an attractive choice for inclusion in aggressive salvage programs aimed at achieving cures of resistant tumors. It may also merit incorporation into frontline treatment protocols. Med. Pediatr. Oncol. 35:468–474, 2000.

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