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Originally published as JCO Early Release 10.1200/JCO.2004.01.946 on March 8 2004 © 2004 American Society of Clinical Oncology.
A Window on Reality?Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD 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.1 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.2 When combined with strong preclinical data showing activity of topotecan against rhabdomyosarcoma xenografts,3 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.4 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.5,6 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.7 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.8 In this phase I study, antitumor activity was observed against several tumor types, including rhabdomyosarcoma.8 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.9 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 question in the affirmative, though the path to this answer is not straightforward. A nearly 50% objective response rate for the topotecan and cyclophosphamide combination appears promising at first glance, but it is difficult to know what response rate should be required for combinations of active agents in newly diagnosed patients. The topotecan and cyclophosphamide response rate is in the same range as that observed after six weeks of treatment with the combination of ifosfamide and doxorubicin, which has demonstrated a 59% objective response rate.10 However, there is a critical piece of missing information in applying these response data to the question of prioritizing the topotecan and cyclophosphamide combination for evaluation in patients with newly diagnosed, nonmetastatic disease. Missing (and probably unknowable) is whether the responses observed in these newly diagnosed patients are occurring for the tumor clones that are ultimately responsible for treatment failure or whether they are restricted to those tumor clones that are successfully eradicated with currently available therapy. The Goldie-Coldman hypothesis assumes that the clone(s) responsible for eventual tumor progression is present at diagnosis and that drug exposure provides the pressure for selection of this resistant cell population. Hence, cytotoxic agents that have little activity against clones that have grown under the selection pressure of standard therapy are unlikely to increase cure rates when added to standard therapy. By comparison, cytotoxic agents with substantial activity against recurrent tumors may be more likely to improve outcome when added to (or substituted for) standard therapy, although a "necessary, but not sufficient" relationship may apply. While the relatively high tumor response rate in newly diagnosed patients described in the Walterhouse report supports the potential promise for the topotecan and cyclophosphamide combination, even stronger evidence for prioritizing this combination comes from the high level of antitumor activity observed for patients with recurrent disease in the conventional phase II trial of the combination.9 The very limited activity of single-agent topotecan compared to the substantial activity of the topotecan and cyclophosphamide combination for patients with recurrent rhabdomyosarcoma supports prioritizing the combination rather than single agent topotecan for phase III evaluation. Another important issue raised by the report of Walterhouse et al concerns the ethics of phase II window evaluations in children with newly-diagnosed cancers for whom standard therapy provides prompt antitumor responses and alleviation of tumor-related symptoms in the majority of patients and for whom the standard therapy results in a relatively low potential for cure.11 Phase II window studies that combine two active agents are more analogous to pilot studies of new regimens and avoid many of the ethical tensions inherent in phase II window studies of single agents with unknown activity. In addition to providing response data, combination phase II window studies can also provide important information about the tolerability of the combination in newly diagnosed patients when incorporated into standard therapy. As with pilot studies, combination phase II window studies must be carefully monitored for excessive toxicity and for inferior outcome compared to that achievable with standard therapy. One curious and unexplained observation from the Walterhouse report is the apparent difference in objective response rates for embryonal histology tumors (four of 14 tumors) compared with alveolar histology tumors (19 of 35 tumors). A lower response rate for embryonal tumors was also observed in the single-agent topotecan phase II window study (4 of 14 for embryonal tumors v 15 of 23 for alveolar tumors). Surprisingly, the response rates for children with recurrent embryonal tumors treated with the topotecan and cyclophosphamide combination (six of nine objective responses) are nominally higher than those described above for children with newly-diagnosed embryonal tumors. These puzzling results may simply reflect the small numbers of patients evaluated and the inherently large confidence intervals around response rate estimates or, alternatively, may reflect unappreciated aspects of the interplay between rhabdomyosarcoma biology and cytotoxic therapy. The likely final chapter in the development of topotecan for rhabdomyosarcoma is being played out now in the D9803 COG phase III trial evaluating the topotecan, cyclophosphamide and vincristine combination when incorporated into standard therapy (see http://www.clinicaltrials.gov/ and search D9803). The study began accrual in 1999 and will complete enrollment in 2004. The study by the COG Soft Tissue Sarcoma Committee reported in this issue of JCO was well designed and well conducted, and it played an important role in the development of the D9803 phase III trial. It demonstrated the tolerability of the experimental arm of the phase III trial, and it documented a reasonably high response rate for the topotecan and cyclophosphamide combination among children with newly diagnosed rhabdomyosarcoma. The data from this report, in combination with the high response rate for the topotecan and cyclophosphamide combination in patients with recurrent disease, support the design of the ongoing phase III study and support the importance of definitively determining the contribution of the topotecan and cyclophosphamide combination when incorporated into standard therapy for children with rhabdomyosarcoma. Authors’ Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Walterhouse DO, Lyden ER, Breitfeld PP, et al: Efficacy of topotecan and cyclophosphamide given as a phase II window in children with newly diagnosed metastatic rhabdomyosarcoma: A report from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group. J Clin Oncol 22:1398-1403, 2004 2. Tubergen DG, Stewart CF, Pratt CB, et al: Phase I trial and pharmacokinetic (PK) and pharmacodynamics (PD) study of topotecan using a five-day course in children with refractory solid tumors: A pediatric oncology group study. J Pediatr Hematol Oncol 18:352-361, 1996[CrossRef][Medline] 3. Houghton PJ, Cheshire PJ, Myers L, et al: Evaluation of 9-dimethylaminomethyl-10-hydroxycamptothecin against xenografts derived from adult and childhood solid tumors. Cancer Chemother Pharmacol 31:229-239, 1992[CrossRef][Medline] 4. Nitschke R, Parkhurst J, Sullivan J, et al: Topotecan in pediatric patients with recurrent and progressive solid tumors: A Pediatric Oncology Group phase II study. J Pediatr Hematol Oncol 20:315-318, 1998[CrossRef][Medline]
5. Bomgaars L, Berg SL, Blaney SM: The development of camptothecin analogs in childhood cancers. Oncologist 6:506-516, 2001 6. Rodriguez-Galindo C, Radomski K, Stewart CF, et al: Clinical use of topoisomerase I inhibitors in anticancer treatment. Med Pediatr Oncol 35:385-402, 2000[CrossRef][Medline] 7. Rowinsky EK, Kaufmann SH: Topotecan in combination chemotherapy. Semin Oncol 24:S20, 1997 (6 suppl 20) 8. Saylors RL III, Stewart CF, Zamboni WC, et al: Phase I study of topotecan in combination with cyclophosphamide in pediatric patients with malignant solid tumors: A Pediatric Oncology Group Study. J Clin Oncol 16:945-952, 1998[Abstract]
9. Saylors RL III, Stine KC, Sullivan J, et al: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: A Pediatric Oncology Group phase II study. J Clin Oncol 19:3463-3469, 2001 10. Sandler E, Lyden E, Ruymann F, et al: Efficacy of ifosfamide and doxorubicin given as a phase II "window" in children with newly diagnosed metastatic rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study Group. Med Pediatr Oncol 37:442-448, 2001[CrossRef][Medline] 11. Smith MA, Anderson B: Phase II window studies: 10 years of experience and counting. J Pediatr Hematol Oncol 23:334-337, 2001[CrossRef][Medline]
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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