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Journal of Clinical Oncology, Vol 25, No 29 (October 10), 2007: pp. 4689-4690 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.6888
Dexrazoxane-Associated Risk for Secondary Malignancies in Pediatric Hodgkin's Disease: A Claim Without EvidenceWindleshaw House, Withyham, East Sussex, United Kingdom To the Editor: The headline of a recent publication in the Journal of Clinical Oncology by Tebbi et al1 proclaims that there is a "dexrazoxane-associated risk for acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and other secondary malignancies in pediatric Hodgkin's disease." Analysis of the size of this risk shows that of 478 patients three patients developed AML/MDS who had chemotherapy with ABVE (doxorubicin, bleomycin, vincristine) or ABVE-PC (etoposide/dose-intensified ABVE with prednisone and cyclophosphamide) and radiotherapy plus dexrazoxane, while two patients who had comparable amounts of cumulative ABVE/ABVE-PC, but no dexrazoxane, also developed AML/MDS. Five patients developed secondary malignant neoplasia (SMN) who had ABVE/ABVE-PC plus dexrazoxane, but these five all had cumulative doses of doxorubicin and/or etoposide substantially above doses known to be leukemogenic.2,3 It is therefore not possible to guess what contribution any additional substance to ABVE may have made to the development of SMN in these patients. The certainty expressed in the title is simply not supported by the evidence. Since the cumulative doses of etoposide, doxorubicin, and cyclophosphamide varied considerably between patients, it is also not possible to say how much interaction there was between the drugs and between the drugs and the patients. It is unknown if the randomization was done properly, the study was run in a blinded fashion, and analyses were conducted appropriately. It appears moreover, contrary to the unequivocal assertion of the title of the Tebbi et al article, that they themselves are aware of the uncertainty surrounding their claim since they state, "...we have not observed this cohort of children [with Hodgkin's disease] long enough to know whether dexrazoxane provided cardiopulmonary protection [which was the objective of the trial], nor were these studies designed for statistical comparison of leukemic and secondary malignant neoplasm risk ..." This disclaimer is presumably meant to explain why they found only one of four statistical tests of cumulative incidence using survival analysis techniques, which is the standard analysis for this type of study, had any degree of statistical significance for the appearance of SMNs or AML/MDS when comparing children with Hodgkin's disease receiving ABVE or ABVE-PC with or without dexrazoxane. Moreover, the single statistically significant finding in these analyses was in a secondary analysis of any SMN as a first event, and neither of the primary analyses within a competing-risks framework showed any statistically significant difference between the dexrazoxane groups. Although the incidence rate was higher in the dexrazoxane group than the nondexrazoxane group, supporting the research hypothesis, the primary statistical test used failed to separate the observed effect from one that might be observed due to random assignment errors. All it takes is a shift in status of one person to drastically change the statistical results. This is a very small basis upon which to make such a large and definite claim as Tebbi et al do. Dexrazoxane is US Food and Drug Administration–approved, established protectant against doxorubicin-induced cardiotoxicity in patients with breast cancer4 and in acute lymphoblastic leukemia of childhood.5 No evidence shows that this protection has impaired the effectiveness (survival) of doxorubicin-treated patients or that it has caused any new or clinically relevant sequelae (infection, hemorrhage, deaths, or necessity for change of dosage). Sixteen clinical trials in seven different countries over the last 10 years involving more than 1,500 patients have not reported a single case of AML as a result of combining dexrazoxane with doxorubicin plus fluorouracil and cyclophosphamide (the FAC regimen).6,7 With no statistical evidence and with no comprehensive consideration of the leukemogenic effect of doxorubicin and of etoposide at cumulative doses considerably below those that they employed, it is surprising that Tebbi et al nevertheless claim that dexrazoxane increased the incidence of AML/MDS. Furthermore, they did not consider the possible leukemogenic effect of G-CSF, which has recently been shown to be a risk factor for AML/MDS.8 In summary, Tebbi et al have no persuasive evidence to support their claim that dexrazoxane was a causative factor in the development of secondary AML/MDS or of secondary malignant neoplasms in pediatric Hodgkin's disease. The title of their article is misleading, unwarranted, and unacceptable. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Tebbi CK, London WB, Friedman D, et al: Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J Clin Oncol 25:493-500, 2007 2. Le Deley MC, Leblanc T, Shamsaldin A, et al: Risk of secondary leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: A case-control study by the Societe Francaise d'Oncologie Pediatrique. J Clin Oncol 21:1074-1081, 2003 3. Tebbi CK, Mendenhall N, London WB, et al: Treatment of stage I, IIA, IIIA1 pediatric Hodgkin disease with doxorubicin, bleomycin, vincristine and etoposide (DBVE) and radiation: A Pediatric Oncology Group (POG) study. Pediatric Blood Cancer 46:198-202, 2006[CrossRef][Medline] 4. Marty M, Espie M, Llombart A, et al: Multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane) in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy. Ann Oncol 17:614-622, 2006 5. Moghrabi A, Levy DE, Asselin B, et al: Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia. Blood 109:896-904, 2007 6. Cvetkovic RS, Scott LJ: Dexrazoxane: A review of its use for cardioprotection during anthracycline chemotherapy. Drugs 65:1005-1024, 2005[CrossRef][Medline] 7. Hellmann K: Dexrazoxane and the ASCO Guidelines for the use of chemotherapy and radiotherapy protectants: A critique. J Clin Oncol 18:2004-2005, 2000 8. Le Deley MC, Suzan F, Cutuli B, et al: Anthracyclines, mitoxantrone, radiotherapy, and granulocyte colony-stimulating factor: Risk factors for leukemia and myelodysplastic syndrome after breast cancer. J Clin Oncol 25:292-300, 2007 Related Reply
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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