A Window on Reality

The report from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group (COG) describing the activity and tolerability of a topotecan and cyclophosphamide combination regimen in children with newly diagnosed metastatic rhabdomyosarcoma represents another important chapter in the development of topotecan in pediatric oncology. The story of topotecan’s development for children with rhabdomyosarcoma illustrates important issues in pediatric drug development, including the contribution of preclinical observations, the relative utility of different clinical trial designs, and the criteria that should be used in prioritizing new agents and combinations of agents for further evaluation. The first chapter in the clinical development of topotecan for children with cancer began in 1992, with the initiation of phase I trials and the observation of antitumor activity in these trials. When combined with strong preclinical data showing activity of topotecan against rhabdomyosarcoma xenografts, this early clinical experience created considerable enthusiasm for further studies of topotecan in children with rhabdomyosarcoma. Preclinical studies have played a central role throughout the pediatric development of topotecan by informing decisions on the schedule of topotecan administration and the potential utility of combining topotecan with other chemotherapy agents. The next chapter in topotecan’s pediatric development was the evaluation of single-agent activity in newly diagnosed patients with high-risk disease (using phase II window designs) and in patients with recurrent disease (using conventional phase II study designs). For newly diagnosed children with high-risk neuroblastoma and metastatic rhabdomyosarcoma, objective response rates between 40% and 50% were observed. By contrast, few objective response rates were observed for children with newly diagnosed osteosarcoma, Ewing sarcoma, and high-grade glioma. For children with recurrent tumors, low objective response rates were observed across all tumor types, including rhabdomyosarcoma, though a substantial number of children with neuroblastoma experienced prolonged stable disease with symptomatic improvement. Comprehensive reviews of the development of topotecan for children with cancer are available for readers interested in details of the multiple relevant preclinical and clinical studies. Phase I testing of combinations of topotecan with DNA-damaging agents or modalities, such as cisplatin, carboplatin, cyclophosphamide, and radiation, was performed more or less in parallel with the pediatric phase II evaluations of single-agent topotecan. Preclinical studies indicated that topoisomerase I inhibitors generally enhanced the antitumor activity of these DNA-damaging agents. A phase I study of the combination of topotecan and cyclophosphamide found that the dose of topotecan had to be reduced by more than 50%, compared with the dose of topotecan tolerated as a single agent. In this phase I study, antitumor activity was observed against several tumor types, including rhabdomyosarcoma. The subsequent phase II trial of the topotecan and cyclophosphamide combination demonstrated substantial activity against multiple tumor types, including a remarkable 66% partial response rate for children with recurrent rhabdomyosarcoma. The report of Walterhouse et al in this issue of the Journal of Clinical Oncology is likely the penultimate chapter in the development of topotecan for children with rhabdomyosarcoma. The primary finding of this report is that the topotecan and cyclophosphamide combination has substantial activity against newly diagnosed metastatic rhabdomyosarcoma, with an overall response rate of 47%. The report also importantly documents the tolerability of adding vincristine to the topotecan and cyclophosphamide combination as well as the tolerability of intercalating this three-drug combination into standard therapy for children with newly-diagnosed rhabdomyosarcoma. Perhaps the most important question raised by this study is whether the objective response rate and the toxicity data described support the prioritization of the topotecan and cyclophosphamide combination for phase III evaluation in children with rhabdomyosarcoma. We answer this JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 8 APRIL 15 2004