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In Reply:

Hasbro Children's Hospital, Warren Alpert Medical School of Brown University, Providence, RI

Louis S. Constine

University of Rochester Medical Center, Rochester, NY

Wendy B. London

Children's Oncology Group, Statistics and Data Center, University of Florida, Gainesville, FL

Richard Sposto

Childrens Hospital, Los Angeles, CA

Debra Friedman

University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA

Cameron K. Tebbi

Tampa Children's Hospital, Tampa, FL

Nancy P. Mendenhall

University of Florida, Gainesville, FL

Doojduen Villaluna

Children's Oncology Group Operations Center, Arcadia, CA

Pedro A. de Alarcon

St Jude Midwest Affiliate, Peoria, IL

Allen Chauvenet

Children's Oncology Group, Arcadia, CA

We appreciate the letter by Lipshultz et al and the opportunity to respond to their comments.

In the attempt to mitigate the potential cardiotoxicity of our novel and effective regimen for children with Hodgkin's lymphoma by incorporating dexrazoxane (DRZ), we observed an unexpected frequency of acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS).¹ More specifically, the addition of DRZ to doxorubicin, bleomycin, vincristine, and etoposide (ABVE) and dose-intensified ABVE with prednisone and cyclophosphamide (ABVE-PC) was associated with an increased risk of second malignant neoplasms (SMNs) and AML/MDS. A postulated mechanism for this association was the cumulative exposure to three topoisomerase II inhibitors (DRZ, doxorubicin, and etoposide), all within 3 hours of one another. Since dexrazoxane affects topoisomerase at a different site than does etoposide,² we hypothesized that simultaneous administration of these multiple inhibitors may have enhanced the risk. This hypothesis is not provable from our data. We also cannot prove the converse—that dexrazoxane is without risk in other regimens.

We are well aware of the use of dexrazoxane as a cardioprotectant in a variety of clinical settings, without any reported increase in secondary malignancies. Indeed, data from other studies in the literature are reassuring. With available evidence, we do concur with Lipshultz et al who cautioned us to refrain from generalizations about DRZ and SMN across studies. However, several of the leukemic chromosomal aberrations noted are similar to those described with exposure to the related agents, razoxane and bimolane.^3,4 Although the statistical strengths of our analyses are limited by the patient numbers and by a study design that was not intended to test such an association, the observation is of sufficient clinical concern that failing to reveal our finding to other oncologists would be irresponsible.

The statistical approaches presented in our paper were selected based on assessment of the most appropriate methodology. Lipshultz et al correctly point out that the Fisher's exact test yields larger P values for the comparison of SMN rates in DRZ versus no DRZ groups treated with ABVE or ABVE-PC than the more appropriate log-rank cumulative incidence comparison (P = .11 v P = .06 and P = .24 v P = .16 for all SMN and AML/MDS, respectively). We do not regard these two results as being substantially different given the conservativeness of the Fisher's exact test⁵ and its limitation of not factoring in the completeness of follow-up or time to event.

We also performed a Poisson regression analysis to see whether the result of the cumulative incidence analysis would hold up under an equally appropriate analysis that would account also for the expected incidence and age of onset of the SMN.⁶ We have reported all of the analyses that we performed originally and those that were added at the suggestion of the reviewers.

Taken as a whole, our analyses suggest that there is some evidence for an association between SMN incidence and use of DRZ, and somewhat less evidence for an association between AML/MDS incidence and use of DRZ. We believe that our conclusion that "Adding DRZ to ABVE and ABVE-PC may have increased the incidence of SMN and AML/MDS" appropriately reflects the strength of the evidence we present.

We appreciate Lipshultz et al's concern that our data might be misinterpreted. Knowing that adverse effects can impact the use of important pharmaceuticals, we would caution that our findings should not be considered evidence against the use of dexrazoxane, except possibly in association with multiple topoisomerase inhibitors. It is our responsibility to report our findings and the statistical strength of the associations. We believe that we have done this with an approach that is both an open and balanced one.

The readers of the Journal of Clinical Oncology will certainly weigh all the results and reach their own conclusions regarding the degree of caution warranted for administration of DRZ with regimens that are clinically appropriate for their patients or patient cohorts.

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[Abstract/Free Full Text]

2. Classen S, Olland S, Berger JM: Structure of the topoisomerase II ATPase region and its mechanism of inhibition by the chemotherapeutic agent ICRF-187. Proc Natl Acad Sci U S A 100:10629-10634, 2003[Abstract/Free Full Text]

3. Baglin TP, Galvin GP, Pollock A: Therapy related acute nonlymphocytic leukemia with inversion of chromosome 16 and a sustained remission. Cancer Genet Cytogenet 27:167-169, 1987[CrossRef][Medline]

4. Xue Y, Lu D, Guo Y, et al: Specific chromosomal translocations and therapy-related leukemia induced by bimolane therapy for psoriasis. Leuk Res 16:1113-1123, 1992[CrossRef][Medline]

5. Engeman R, Swanson GD: Alternatives to Fisher exact test for analyzing 2x2 tables with small-cell sizes. Biometrics 46:267-268, 1990

6. Yasui Y, Liu Y, Neglia JP, et al: A methodological issue in the analysis of second-primary cancer incidence in long-term survivors of childhood cancers. Am J Epidemiol 158:1108-1113, 2003[Abstract/Free Full Text]

Related Correspondence

• Dexrazoxane-Associated Risk for Secondary Malignancies in Pediatric Hodgkin's Disease: A Claim Without Compelling Evidence
  Steven E. Lipshultz, Stuart R. Lipsitz, and Endel John Orav
  JCO 2007 25: 3179 [Full Text]

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