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© 2000 American Society for Clinical Oncology
Cyclophosphamide and Etoposide for Pediatric Solid TumorsSt Jude Children’s Research Hospital Memphis, TN To the Editor:We read with interest the report by Mantadakis et al of a study in which 17 children with a variety of solid tumors were treated with fractionated cyclophosphamide and etoposide.1 The authors concluded that this drug combination is active and tolerable in this patient population and that it merits further testing. Although we do not disagree entirely with the latter statement, we wish to express concern about this study’s design, the authors’ selective citation of the literature on ifosfamide, and the study’s conclusions. We believe that the authors were mistaken in terming their study a "phase II window" trial for patients with advanced or refractory solid tumors. Phase II window studies are generally developed on the basis of compelling clinical or preclinical evidence of activity and are aimed at estimating response rates in a homogeneous group of patients.2 Optimally, a two-stage design is used to evaluate the efficacy of a specific drug or drug combination. Because small numbers of patients are enrolled, it is customary to construct confidence intervals around the estimate to better define the true rate of response to the agent(s) tested. In our opinion, the report by Mantadakis et al fails to adequately address several of these basic principles of study design. First, the study population was extremely heterogeneous. Five of the patients had received previous treatment, and six different histologic tumor types were included. Second, the number of patients treated (17) was too small to allow meaningful conclusions about the true rate of response. Further, six of the patients treated had newly diagnosed, nonmetastatic tumors of histiologic types that are known to respond to standard combination chemotherapy. It is unclear whether these patients were offered the option of receiving standard treatment instead of the cyclophosphamide and etoposide combination at the time of diagnosis and whether patients who responded to the cyclophosphamide-etoposide combination received this drug pair during continuation therapy, as suggested by the Cancer Therapy Evaluation Program of the National Cancer Institute.3 We question the appropriateness of this kind of "window testing" in newly diagnosed patients whose 5-year survival estimate is expected to exceed 65% with standard approaches.4-6 The authors state that their patients’ overall rate of response to cyclophosphamide and etoposide (59%) is comparable to response rates obtained with ifosfamide and etoposide. We believe that the authors underestimate the efficacy of ifosfamide in the treatment of a variety of pediatric solid tumors. They fail to mention the response rate of 96% (95% confidence interval, 80% to 99%) obtained with ifosfamide and etoposide in patients with newly diagnosed Ewing’s sarcoma of bone7 and the significant improvement in outcome seen when this pair of drugs was added to standard therapy for patients with nonmetastatic Ewing’s sarcoma.4 Further, the 79% rate of response in the Intergroup Rhabdomyosarcoma Study IV phase II window trial of ifosfamide and etoposide for patients with metastatic rhabdomyosarcoma8 was among the highest response rates ever seen in an Intergroup Rhabdomyosarcoma Study Group trial for newly diagnosed rhabdomyosarcoma, and the outcome for these patients was better than that seen with other drug combinations. Finally, the fact that three of the five patients with relapsed disease responded to cyclophosphamide and etoposide is not entirely surprising, given that two of the three responders had rhabdomyosarcoma, had never received etoposide, and had limited prior exposure to cyclophosphamide. Responses to cyclophosphamide-based regimens have been documented in children with recurrent rhabdomyosarcoma.9 On the basis of our observations of this article, we suggest that the results of this trial be interpreted with caution. REFERENCES
1.
Mantadakis E, Herrera L, Leavey PJ, et al: Fractionated cyclophosphamide and etoposide for children with advanced or refractory solid tumors: A phase II window study. J Clin Oncol 18: 2576-2581, 2000 2. Simon R: How large should a phase II trial of a new drug be? Cancer Treat Rep 71: 1079-1085, 1987[Medline] 3. Cancer Therapy Evaluation Program: Policies, guidelines & procedures: Phase II window studies in pediatric oncology meeting report. Available at: http://ctep.info.nih.gov/Policies/Phase2.htm. Accessed September 20, 2000 4. Grier H, Krailo M, Link M, et al: Improved outcome in non-metastatic Ewing’s sarcoma (EWS) and PNET of bone with the addition of ifosfamide (I) and etoposide (E) to vincristine (V), Adriamycin (Ad), cyclophosphamide (C), and actinomycin (A): A Childrens Cancer Group (CCG) and Pediatric Oncology Group (POG) report. Proc Am Soc Clin Oncol 13: 421, 1994 (abstr 1443) 5. Goorin A, Baker A, Gieser P, et al: No evidence for improved event free survival (EFS) with presurgical chemotherapy (PRE) for non-metastatic extremity osteogenic sarcoma (OGS): Preliminary results of randomized Pediatric Oncology Group (POG) trial 8651. Proc Am Soc Clin Oncol 14: 444, 1995 (abstr 1420)
6.
Baker KS, Anderson JR, Link MP, et al: Benefit of intensified therapy for patients with local or regional embryonal rhabdomyosarcoma: Results from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 18: 2427-2434, 2000
7.
Meyer WH, Kun L, Marina N, et al: Ifosfamide plus etoposide in newly diagnosed Ewing’s sarcoma of bone. J Clin Oncol 10: 1737-1742, 1992 8. Ruymann F, Crist W, Wiener E, et al: Comparison of two doublet chemotherapy regimens and conventional radiotherapy in metastatic rhabdomyosarcoma: Improved overall survival using ifosfamide/etoposide compared to vincristine/melphalan in IRSG-IV. Proc Am Soc Clin Oncol 16: 521a, 1997 (abstr 1874) 9. 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]
ResponseChildren’s Medical Center of Dallas Dallas, TX In Reply:The purpose of our study was to demonstrate that fractionated cyclophosphamide, administered with etoposide, is safe and effective in children with a variety of malignant solid tumors.1 Drs Spunt and Pappo are correct; this was not a classic phase II window trial. This therapy was offered to patients with (1) recurrent or secondary solid tumors (n = 6), (2) metastatic disease at diagnosis (n = 6), (3) diagnoses and/or concurrent problems that precluded entry onto a cooperative group study (n = 4; synovial cell sarcoma, peripheral nerve sheath tumor, epithelioid sarcoma, and Ewing’s sarcoma of the maxillary sinus in a child with altered mental status secondary to acute disseminated encephalomyelitis) and (4) an Askin tumor filling the left hemithorax (this child was entered at the investigator’s discretion (n = 1). As we stated in the article, and as Drs Spunt and Pappo point out, this is a small and heterogeneous population, with almost half of the patients being heavily pretreated. It is not surprising then that the studies referred to by Drs Spunt and Pappo2-4 describe better response rates after the administration of ifosfamide and etoposide to newly diagnosed, chemotherapy-naive children with malignancies known to be sensitive to alkylating agents. Ifosfamide is an alkylating agent with impressive activity against a variety of pediatric malignancies. Randomized trials comparing ifosfamide and cyclophosphamide have been few, however, and have not demonstrated the superiority of ifosfamide.5,6 Although an ifosfamide dose of 9.0 g/m2 is considered "equivalent" to a 2.1-g/m2 dose of cyclophosphamide, most studies have used different schedules, with ifosfamide typically given over 5 days versus 1 to 3 days for cyclophosphamide. Baker et al6 recently reported the results from the IRS IV trial for children with local or regional embryonal rhabdomyosarcoma. Event-free survival improved from 72% on IRS III to 78% on IRS IV. The improvement was attributed to a doubling of the dose-intensity of cyclophosphamide or ifosfamide equivalent, with no difference observed among the three randomized chemotherapy arms: vincristine and dactinomycin plus cyclophosphamide or ifosfamide versus the third regimen, vincristine, ifosfamide, and etoposide. Moreover, two European trials7,8 failed to demonstrate an improvement in event-free survival after the addition of ifosfamide/etoposide to a four-drug regimen for the treatment of Ewing’s sarcoma, despite the success with this pair, described by Grier et al in 1994.2 In conclusion, the absence of a comparative study, incorporating pharmacokinetics designed to match the area under the concentration curve for the active species, leaves us without the data needed to demonstrate that ifosfamide is the superior choice. We believe that the pediatric oncology community should critically reassess the risk-to-benefit ratio of the two oxazaphosphorines, especially now that investigators at St Jude Children’s Research Hospital9 and the United Kingdom Children’s Cancer Study Group Late Effects Group have described chronic, ifosfamide-related, glomerular and proximal renal tubular toxicity.10 REFERENCES 1. Mantadakis E, Herrera L, Leavey PJ, et al: Fractionated cyclophosphamide and etoposide for children with advanced or refractory solid tumors: A phase II window study. J Clin Oncol 18: 2576-2581, 2000 2. Grier H, Krailo M, Link M, et al: Improved outcome in non-metastatic Ewing’s sarcoma (EWS) and PNET of bone with addition of ifosfamide (I) and etoposide (E) to vincristine (V), Adriamycin (Ad), cyclophosphamide (C), and actinomycin (A): A Childrens Cancer Group (CCG) and Pediatric Oncology Group (POG) report. Proc Am Soc Clin Oncol 13: 421, 1994 (abstr 1443) 3. Meyer WH, Kun L, Marina N, et al: Ifosfamide plus etoposide in newly diagnosed Ewing’s sarcoma of bone. J Clin Oncol 10: 1737-1742, 1992 4. Ruymann F, Crist W, Wiener E, et al: Comparison of two doublet chemotherapy regimens and conventional radiotherapy in metastatic rhabdomyosarcoma: Improved overall survival using ifosfamide/etoposide compared to vincristine/melphalan in IRSG-IV. Proc Am Soc Clin Oncol 16: 521a, 1997 (abstr 1874) 5. Bramwell VHC, Mouridsen HT, Santoro A, et al: Cyclophosphamide versus ifosfamide: Final report of a randomized phase II trial in adult soft tissue sarcomas. Eur J Cancer Clin Oncol 23: 311-321, 1987[Medline] 6. Baker KS, Anderson JR, Link MP, et al: Benefit of intensified therapy for patients with local or regional embryonal rhabdomyosarcoma: Results from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 18: 2427-2434, 2000
7.
Oberlin O, Habrand JL, Zucker JM, et al: No benefit of ifosfamide in Ewing’s sarcoma: A nonrandomized study of the French Society of Pediatric Oncology. J Clin Oncol 10: 1407-1412, 1992 8. Bacci G, Picci P, Ferrari S, et al: Neoadjuvant chemotherapy for Ewing’s sarcoma of bone. Cancer 82: 1174-1183, 1998[Medline] 9. Marina NM, Poquette CA, Cain AM, et al: Comparative renal tubular toxicity of chemotherapy regimens including ifosfamide in patients with newly diagnosed sarcomas. J Pediatr Hematol Oncol 22: 112-118, 2000[Medline] 10. Skinner R, Cotterill SJ, Stevens MC: Risk factors for nephrotoxicity after ifosfamide treatment in children: A UKCCSG Late Effects Group Study—United Kingdom Children’s Cancer Study Group. Br J Cancer 82: 1636-1645, 2000[Medline]
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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