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Journal of Clinical Oncology, Vol 25, No 29 (October 10), 2007: pp. 4690-4691 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.1292
In ReplyHasbro Children's Hospital, Warren Alpert Medical School of Brown University, Providence, RI
University of Rochester Medical Center, Rochester, NY
Children's Oncology Group, Statistics and Data Center, University of Florida, Gainesville, FL
Childrens Hospital, Los Angeles, CA
University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA
Tampa Children's Hospital, Tampa, FL
University of Florida, Gainesville, FL
Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD
St Jude Midwest Affiliate, Peoria, IL
City of Hope, Population Sciences Division, Duarte, CA
Children's Oncology Group, Arcadia, CA We appreciate the interest in our report and welcome the opportunity to clarify any misconceptions. Dexrazoxane is recognized as a cardioprotectant for anthracyline-associated toxicity. In our study,1 we reported a concerning finding of a higher incidence of second malignant neoplasms (SMN), particularly therapy-related acute myeloid leukemia (AML) in patients randomly assigned to receive three topoisomerase inhibitors simultaneously (doxorubicin, etoposide, and dexrazoxane) in comparison with those who received only doxorubicin and etoposide. Although we had no antecedent plan to test the hypothesis that dexrazoxane may increase the risk of SMN/AML, the magnitude of the difference in incidence we observed and the biologic plausibility that inhibition of topoisomerase II by dexrazoxane may compound risks associated with doxorubicin and etoposide, support the validity of this hypothesis. Given the concern brought about by the statistical evidence, it would be irresponsible if we did not make the oncology community aware of these events. We do not claim that these findings invoke dexrazoxane as a carcinogenic agent, or suggest that it has no clinical applicability. In particular, our study does not provide any evidence regarding risk of SMN for those patients receiving dexrazoxane and high-dose anthracyclines without concurrent etoposide. The statistical methods presented in our article include those originally performed by our statisticians, as well as analyses requested by reviewers. We stand by our report, the statistical methodologies, and our conclusions. To most directly respond to Dr Hellman's concerns, we should clarify and correct some factual errors on which his comments are based. We present a point-by-point response to his concerns. Dr Hellman states that there were three patients with AML/myelodysplastic syndrome (MDS) among those receiving dexrazoxane, versus two among those who did not. This is not correct. In total, six patients developed AML/MDS among those receiving dexrazoxane, compared with two among those who did not. There were five patients with AML/MDS as a first event among those receiving dexrazoxane, compared with one patient with AML/MDS among those who did not receive it. Dr Hellmann states that there were five patients who developed SMN with ABVE/ABVE-PC (doxorubicin, bleomycin, vincristine, and etoposide/dose-intensified ABVE with prednisone and cyclophosphamide) plus dexrazoxane. This is also not correct. In fact, eight patients developed SMN after ABVE/ABVE-PC plus dexrazoxane, versus two after ABVE/ABVE-PC without dexrazoxane. He also states that all had cumulative doses of doxorubicin and/or etoposide that were substantially above doses known to be leukemogenic. This is not supported by current evidence in our study, nor in other analyses of secondary leukemia. Although both of these agents have been associated with SMN, the cumulative doses used in this trial are generally not associated with the magnitude of risk noted on the dexrazoxane arm. The cumulative doses of anthracycline and etoposide did not differ between randomized arms, which allowed the direct assessment of the additional impact of dexrazoxane. Dr Hellman questions whether random assignment was done properly, whether the study was run in a blinded fashion, and whether analyses were conducted appropriately. This was a Pediatric Oncology Group (POG)/Children's Oncology Group trial—the major cooperative trial group for children with cancer in the United States and Canada, with collaboration of several international centers as well. Random assignments were done in a standardized, well-documented fashion. Treatment assignment was not blinded, but we do not believe that the end point of SMN could have been biased by knowledge of the treatment assignment, as follow-up methodology did not differ between the randomized arms. Our statistical methodology and its limitations are carefully described in the article. We observed that patients randomly assigned to receive dexrazoxane experienced a higher cumulative incidence of SMN, and the standardized incidence ratio of SMN as a first event was higher—findings that approached statistical significance. The differences in cumulative incidence of MDS/AML and of any SMN were similar in magnitude and direction, though they did not achieve statistical significance. These findings suggest that dexrazoxane may have increased the risk of the SMN, including MDS/AML in this cohort. We would be irresponsible if we were not to make clinicians aware of these findings. This was not a "research hypothesis." We report an unexpected pattern of very serious adverse events. It is not uncommon to report toxicity associated with clinical trials, particularly when there is serious potential risk. Dr Hellman states that dexrazoxane is US Food and Drug Administration–approved for use in childhood ALL. This is not correct. It was used by the Dana-Farber Cancer Institute Consortium as a randomized study question on protocol 95-01.2 Use of dexrazoxane is not standard of care for the treatment of children with ALL. We have reported an increased risk of hematopoietic toxicity in POG 9425/26, with increased infectious risk in POG 9425.3 Swain et al also noted an increased hematopoietic risk in their trials, with very clearly defined evidence.4 Dr Hellman is aware of this, as he refuted their results in a Letter to the Editor in the Journal of Clinical Oncology.5 We have hypothesized that the risks noted are the result of combining dexrazoxane (a topoisomerase II inhibitor) with both etoposide and doxorubicin, which also inhibit topoisomerase II. We are quite aware of the potential benefit exhibited by dexrazoxane in other published studies (eg, of pediatric sarcoma).6 All patients on these studies received identical amounts of granulocyte-colony stimulating factor. The use of granulocyte-colony stimulating factor cannot explain the difference in risk of SMN between the randomized study arms. Attempts to hide or to mis-state data serve no purpose. Knowledge of potential risk is essential to ensure the safety of patients and to further the science of oncology. Based on our study, we would not recommend the use of dexrazoxane in patients receiving doxorubicin and etoposide as used in our studies. We trust the ability of our colleagues to evaluate the data and to make the best decisions for their own patients and in the design of future clinical trials. AUTHORS’ 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. 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 3. Schwartz CL, Tebbi CK, London WB, et al: Enhanced toxicity in pediatric Hodgkin disease (HD) patients treated with DBVE or DBVE-PC and Dexrazoxane (DXR). Blood 102:143a-144a, 2003 4. Swain SM, Whaley FS, Gerber MC, et al: Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 15:1318-1332, 1997 5. Hellmann K: Dexrazoxane and the ASCO guidelines for the use of chemotherapy and radiotherapy protectants: A critique. J Clin Oncol 18:2004-2006, 2000 6. Wexler LH, Andrich MP, Venzon D, et al: Randomized trial of the cardioprotective agent ICRF-187 in pediatric sarcoma patients treated with doxorubicin. J Clin Oncol 14:362-372, 1996 Related Correspondence
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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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