Cyclophosphamide and Etoposide for Pediatric Solid Tumors
Authors: Sheri L. Spunt, Alberto S. Pappo, Naomi J. Winick
Journal: Journal of Clinical Oncology (2000)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2000.18.21.3741 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11054452 Cyclophosphamide and Etoposide for Pediatric Solid Tumors Sheri L. SpuntxSheri L. SpuntSearch for articles by this author , Alberto S. PappoxAlberto S. PappoSearch for articles by this author Naomi J. WinickxNaomi J. WinickSearch for articles by this author Show More St Jude Children’s Research Hospital Memphis, TNChildren’s Medical Center of Dallas Dallas, TX https://doi.org/10.1200/JCO.2000.18.21.3741 First Page Full Text PDF Figures and Tables © 2000 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01112000In 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 1994.2In 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.101. 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:: 2576,2000-2581, Link, Google Scholar2. 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) Google Scholar3. Meyer WH, Kun L, Marina N, et al: Ifosfamide plus etoposide in newly diagnosed Ewing’s sarcoma of bone. J Clin Oncol 10:: 1737,1992-1742, Link, Google Scholar4. 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) Google Scholar5. 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:: 311,1987-321, Crossref, Medline, Google Scholar6. 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:: 2427,2000-2434, Link, Google Scholar7. 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:: 1407,1992-1412, Link, Google Scholar8. Bacci G, Picci P, Ferrari S, et al: Neoadjuvant chemotherapy for Ewing’s sarcoma of bone. Cancer 82:: 1174,1998-1183, Crossref, Medline, Google Scholar9. 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:: 112,2000-118, Crossref, Medline, Google Scholar10. 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:: 1636,2000-1645, Crossref, Medline, Google Scholar