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Dexrazoxane-Associated Risk for Secondary Malignancies in Pediatric Hodgkin's Disease: A Claim Without Compelling Evidence

Department of Pediatrics, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL

Stuart R. Lipsitz

Division of General Internal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

Endel John Orav

Division of General Internal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

To the Editor:

The title of a recent article by Tebbi et al¹ claims that dexrazoxane poses a risk, and that it is responsible for a higher incidence of secondary acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and other second malignant neoplasms (SMNs) in children with Hodgkin's disease (HD) treated with dexrazoxane plus doxorubicin, bleomycin, vincristine, and etoposide (ABVE) or dose-intensified ABVE with prednisone and cyclophosphamide (ABVE-PC) as well as radiotherapy (POG 9426 [low-stage HD] and 9425 [advanced-stage HD]). This claim is based on 10 SMNs (including eight AML/MDS) in 478 patients. Differences in the incidence of SMNs between children randomly assigned to receive dexrazoxane versus no dexrazoxane concomitantly with chemotherapy to evaluate its efficacy as a cardiopulmonary protectant show no statistical significance by simple Fisher's exact tests (of 239 patients, eight [3.35%] v two [0.84%] with SMNs, respectively, and P = .11; six [2.51%] v two [0.84%] with AML/MDS, respectively, and P = .24), nor by the more conventional and appropriate time-to-event analysis used by the authors (P = .06 for SMNs; P = .16 for AML/MDS). Only after adjusting for race, age, and sex in a different analysis using a Poisson regression model were the authors able to achieve a P value below .05 for any type of SMN (P = .02 for SMNs; P = .10 for AML/MDS), even though the authors demonstrated no imbalance between arms for race, age, or sex. We would regard this as scant statistical evidence, particularly in a trial that, as the authors observe, was not "designed for statistical comparison of leukemia and SMN risk."¹

Dexrazoxane is a US Food and Drug Administration–approved, established protectant against doxorubicin-induced cardiotoxicity in patients with breast cancer² and is also cardioprotective in acute lymphoblastic leukemia of childhood,³ as well as with other malignancies.⁴ 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). Some 16 clinical trials in seven different countries over the past 10 years involving more than 500 patients have not reported a single case of AML as a result of combining dexrazoxane with doxorubicin plus fluorouracil and cyclophosphamide (the FAC regime).⁴

In summary, Tebbi et al have very weak statistical evidence and no precedent in the existing literature to support the very strong claim in the title of their article that dexrazoxane was associated with the development of secondary AML/MDS or of SMNs in pediatric HD. Tebbi et al conclude their abstract by stating, "Adding DRZ [dexrazoxane] to ABVE and ABVE-PC may have increased the incidence of SMN and AML/MDS."¹ This goes beyond the "dexraxozane-associated risk" statement in the title,¹ which is a weak association, as noted in this letter, and actually suggests a causative effect. We take issue with both the title and this conclusion suggesting causation. This is misleading, unwarranted, and therefore unacceptable. Further, in the absence of complete long-term follow-up of these patients to assess the balance of SMNs, adverse outcomes, toxicities, and late effects on overall outcome, it is not possible to make evidence-based recommendations about the use of dexrazoxane for patients treated on these protocols. More important, data-driven generalization of these results to other patients is also not possible.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Steven E. Lipshultz, Chiron (C) Stock Ownership: None Honoraria: Steven E. Lipshultz, Chiron Research Funding: Steven E. Lipshultz, Pfizer, Novartis Expert Testimony: None Other Renumeration: None

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[Abstract/Free Full Text]

2. 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[Abstract/Free Full Text]

3. 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[Abstract/Free Full Text]

4. Cvetkovic RS, Scott LJ: Dexrazoxane: A review of its use for cardioprotection during anthracycline chemotherapy. Drugs 65:1005-1024, 2005[CrossRef][Medline]

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Related Reply

• In Reply:
  Cindy L. Schwartz, Louis S. Constine, Wendy B. London, Richard Sposto, Debra Friedman, Cameron K. Tebbi, Nancy P. Mendenhall, Doojduen Villaluna, Pedro A. de Alarcon, and Allen Chauvenet
  JCO 2007 25: 3180 [Full Text]

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• Dexrazoxane-Associated Risk for Acute Myeloid Leukemia/Myelodysplastic Syndrome and Other Secondary Malignancies in Pediatric Hodgkin's Disease
  Cameron K. Tebbi, Wendy B. London, Debra Friedman, Doojduen Villaluna, Pedro A. De Alarcon, Louis S. Constine, Nancy Price Mendenhall, Richard Sposto, Allen Chauvenet, and Cindy L. Schwartz
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