This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Barry, E. V. Articles by Silverman, L. B. Search for Related Content PubMed PubMed Citation Articles by Barry, E. V. Articles by Silverman, L. B. Social Bookmarking                            What's this?

Absence of Secondary Malignant Neoplasms in Children With High-Risk Acute Lymphoblastic Leukemia Treated With Dexrazoxane

Elly V. Barry, Lynda M. Vrooman, Suzanne E. Dahlberg, Donna S. Neuberg, Barbara L. Asselin, Uma H. Athale, Luis A. Clavell, Eric C. Larsen, Albert Moghrabi, Yvan Samson, Marshall A. Schorin, Harvey J. Cohen, Steven E. Lipshultz, Stephen E. Sallan, Lewis B. Silverman

From the Departments of Pediatric Oncology, Biostatistics and Computational Biology, Dana-Farber Cancer Institute; Division of Hematology/Oncology, Children's Hospital; Harvard Medical School, Boston, MA; Division of Pediatric Oncology, University of Rochester Medical Center, Rochester, NY; Division of Pediatric Hematology/Oncology, McMaster University, Hamilton, Ontario; Division of Hematology and Oncology, Hospital Sainte-Justine, University of Montreal; Centre Hospitalier Universitaire de Quebec, Quebec, Canada; Division of Pediatric Oncology, San Jorge Children's Hospital, San Juan, Puerto Rico; Department of Pediatric Hematology/Oncology, Maine Children's Cancer Program, Scarborough, ME; Section of Pediatric Hematology/Oncology, Inova Fairfax Hospital for Children, Falls Church, VA; Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA; and Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL

Corresponding author: Elly V. Barry, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: elly_barry{at}dfci.harvard.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Purpose Dexrazoxane is a drug used to prevent anthracycline-induced cardiotoxicity. A recent report found an association between the use of dexrazoxane and the risk of developing secondary malignant neoplasms (SMNs) in children with Hodgkin's disease. We report the absence of an association of SMNs in children with acute lymphoblastic leukemia (ALL) treated on Dana-Farber Cancer Institute ALL Consortium Protocol 95-01.

Patients and Methods Two hundred five children with high-risk (HR) ALL were randomly assigned to receive doxorubicin alone (n = 100) or doxorubicin with dexrazoxane (n = 105) during the induction and intensification phases of multiagent chemotherapy. We compared incidence of SMNs in these two groups.

Results With a median follow-up of 6.2 years, no differences in the incidence of SMNs were noted between the group that received dexrazoxane and the group that did not (P = .66). One SMN (a melanoma located outside of the cranial radiation field) occurred in a patient who was randomly assigned to doxorubicin alone. No SMNs were observed in patients randomly assigned to receive dexrazoxane.

Conclusion Dexrazoxane was not associated with an increased risk of SMNs in children treated for HR ALL. Given the potential importance of dexrazoxane as a cardioprotectant, we recommend that dexrazoxane continue to be used and studied in doxorubicin-containing pediatric regimens.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Anthracyclines, such as doxorubicin, have broad activity against a variety of cancers.^1-7 However, such drugs have been associated with toxic effects on the myocardium.^8,9 One approach to prevent anthracycline-induced cardiac damage has been the use of cardioprotective agents, such as dexrazoxane.

Dexrazoxane, a bisdioxopiperazine compound introduced in the 1970s as an anticancer agent, acts by inhibiting topoisomerase II, scavenging free radicals, and chelating heavy metals.^10-12 Dexrazoxane binds to intracellular iron and prevents the formation of free radicals.^12,13 As a result, the myocardial free iron pool is reduced and iron is prevented from complexing with anthracyclines and causing cellular damage.¹⁴

The first clinical trials examining the role of dexrazoxane as a cardioprotectant were conducted in women with advanced breast cancer.¹⁵ Dexrazoxane had a marked cardioprotective effect in preventing deterioration in cardiac ejection fraction and also prevented the development of clinical congestive heart failure. Subsequent studies in other adult cancer patients confirmed that dexrazoxane reduced anthracycline-associated cardiotoxicity and allowed higher cumulative doses of anthracyclines to be used without having an adverse impact on antitumor activity.^16,17

Between 1996 and 2000, we conducted one of the first randomized studies of the cardioprotective effects of dexrazoxane in pediatric patients. On Dana-Farber Cancer Institute (DFCI) Acute Lymphoblastic Leukemia (ALL) Consortium Protocol 95-01, children with high-risk (HR) ALL were randomly assigned to receive either doxorubicin alone or dexrazoxane before each dose of doxorubicin.¹⁸ We have previously reported that dexrazoxane significantly reduced elevations of troponin-T, a marker of acute cardiomyocyte injury.¹⁹ On the basis of these results, since 2000, we have administered dexrazoxane to all HR children with ALL receiving high cumulative doses of doxorubicin.

Recently, the Children's Oncology Group reported that dexrazoxane was associated with a higher risk for developing secondary malignant neoplasms (SMNs), including acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS), in children treated for Hodgkin's disease (HD).²⁰ That study was the first to report such an association. As a result, we have updated our outcome results from Protocol 95-01 and present evidence that dexrazoxane, used as a cardioprotectant in children with ALL, is not associated with SMNs.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Patients
DFCI-ALL Consortium Protocol 95-01 enrolled patients between January 1996 and September 2000. Participating institutions included DFCI and Children's Hospital Boston (Boston, MA), University of Rochester (Rochester, NY), McMaster University (Hamilton, Ontario, Canada), San Jorge Children's Hospital/University of Puerto Rico (San Juan, Puerto Rico), Hospital Sainte-Justine (Montreal, Quebec, Canada), Maine Children's Cancer Program (Portland, ME), Ochsner Clinic (New Orleans, LA), Mount Sinai Medical Center (New York, NY), and Le Centre Hospitalier de L'Universite (Laval, Quebec, Canada). Institutional review board approval was obtained at all participating institutions, and informed consent was obtained for each patient before initiation of therapy.

A total of 498 children, 0 to 17.99 years of age, with newly diagnosed ALL were enrolled. Informed consent was obtained from parents and/or guardians before initiation of therapy. Three patients were deemed ineligible after enrollment, one due to HIV positivity, one due to prior steroid treatment, and one due to a diagnosis of Burkitt lymphoma. Three patients withdrew consent for further treatment, and one patient was withdrawn as a result of inadequate consent. Therefore, a total of 491 assessable patients were available for analysis.

Patients were stratified into two risk groups, standard risk (SR) and HR, according to NCI-recommended criteria on the basis of characteristics at the time of diagnosis.²¹ HR was defined as age younger than 1 year or older than 10 years; WBC 50,000/µL; and the presence of T-cell immunophenotype, the Philadelphia chromosome, a radiologic mediastinal mass, or evidence of CNS leukemia (defined as CNS-2 or CNS-3).²² All other patients were classified as SR.

Among the 491 assessable subjects, 219 were classified as HR. Fourteen HR patients declined random assignment and were directly assigned to receive doxorubicin without dexrazoxane. Of the remaining 205 HR patients, 100 (49%) were randomly assigned to receive doxorubicin alone, and 105 (51%) were randomly assigned to receive doxorubicin with dexrazoxane during the induction and intensification phases of therapy. As of April 2007, median follow-up for this group of patients was 6.2 years.

Treatment
Details of the treatment regimen have been previously published.¹⁸ Briefly, therapy for the HR arm consisted of four phases: (1) a five-drug induction regimen (vincristine, prednisone, doxorubicin, high-dose methotrexate, and asparaginase); (2) a 2-week CNS-intensification phase (consisting of four doses of intrathecal chemotherapy and 18 Gy cranial radiation); (3) a 30-week intensification phase consisting of weekly asparaginase and cycles once every 3 weeks of vincristine, prednisone, mercaptopurine, and doxorubicin 30 mg/m²/dose to a cumulative dose of 300 mg/m²; and (4) a continuation phase consisting of cycles once every 3 weeks of vincristine, prednisone, mercaptopurine, and methotrexate. Therapy was continued until 24 months of complete continuous remission. For the patients randomly assigned to receive dexrazoxane, a dose of 300 mg/m² was administered by rapid intravenous infusion immediately before each dose of doxorubicin during the induction and intensification phases.

Statistical Methods
Differences in baseline characteristics between groups were compared using Fisher's exact tests for categoric data and Kruskal-Wallis tests for continuous data. Outcome events included death during induction, failure to achieve complete remission (CR), death during remission, relapse, and occurrence of SMN. Event-free survival (EFS) was defined as the time from CR to the first outcome event. Induction failures and induction deaths were considered events at time zero. Leukemia-free survival (LFS) was defined as the time from CR to relapse, and overall survival (OS) was defined as the time from the start of treatment to death from any cause. The Kaplan-Meier method was used to estimate the distribution of EFS, LFS, and OS, and univariate associations between groups were tested using log-rank tests.^23,24 All tests conducted were two-sided at the .05 significance level. There were no corrections for multiple comparisons.

Competing Risks Analysis
We estimated the cumulative incidence of SMNs among HR patients on Protocol 95-01 who achieved CR. A total of 195 patients were included in this analysis after excluding induction failures and deaths during induction (n = 9), as well as one patient for whom the date of CR was not available. The primary event of interest was defined as the occurrence of any SMN, and competing events were defined as relapse and death in remission from any cause. Time to event was calculated from the date of CR to the date of the first event, and patients who did not experience one of the events were censored at the last date of follow-up. All calculations, including treatment comparisons, were made using the competing risks methodology of Gray.²⁵

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Patient Characteristics
The presenting characteristics of the 205 randomly assigned HR patients are listed in Table 1. Patients assigned to either doxorubicin alone or doxorubicin plus dexrazoxane did not differ in the presenting features, including age at diagnosis, sex, immunophenotype, and presenting WBC count.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Event-free survival (EFS) among 205 children with high-risk (HR) acute lymphoblastic leukemia (ALL) treated on Dana-Farber Cancer Institute–ALL Consortium Protocol 95-01. The 5-year EFS ± SE was 77% ± 4% for patients randomly assigned to doxorubicin alone, and 76% ± 4% for patients randomly assigned to doxorubicin plus dexrazoxane. The difference was not statistically significant (P = .95).

With 6.2 years median follow-up, the 5-year cumulative incidence of SMN was 0.2% (95% CI, 0% to 0.65%) for all 491 patients enrolled onto Protocol 95-01, and was 0.5% (95% CI, 0% to 1.5%) for all HR patients. The 5-year cumulative incidence of SMN for HR patients randomly assigned to receive dexrazoxane was zero. There was no significant difference in the occurrence of SMN based on dexrazoxane randomization (P = .56).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Dexrazoxane is a cardioprotective agent that has been shown to prevent anthracycline-induced cardiotoxicity.^15-17 The DFCI-ALL Consortium has been studying the cardioprotective effects of dexrazoxane since 1996. In addition to documenting the short-term prevention of cardiac injury, as evidenced by reduction of troponin-T elevations,¹⁹ we have demonstrated that no difference exists in the 5-year EFS between children who received doxorubicin and dexrazoxane and those who received doxorubicin alone (76% v 77%; P = .99).¹⁸ We now report the absence of an association between the use of dexrazoxane and the development of SMNs in these patients.

The latter finding differs from that of Tebbi et al,²⁰ who reported the results of a randomized study of the cardioprotectant dexrazoxane in pediatric patients with HD. Patients with low-risk HD received treatment with doxorubicin, bleomycin, vincristine, and etoposide; HR patients received similar therapy that was further intensified with prednisone and cyclophosphamide. Patients were randomly assigned to receive dexrazoxane (300 mg/m² intravenously, given on any day that doxorubicin or bleomycin was administered), to evaluate its cardiopulmonary protective effect. All patients received low-dose, involved-field or regional-field radiation. Investigators found an increased incidence of SMNs in the dexrazoxane-treated recipients, after a median follow-up time of 4.8 years. Specifically, among 478 HR and low-risk patients with HD, a total of 10 SMNs were noted: eight occurred in the dexrazoxane-treated group and two occurred in the group treated without dexrazoxane. Of the 10 SMNs, eight patients developed either AML or MDS, and two others developed solid tumors (a thyroid papillary carcinoma and an osteosarcoma). Of note, two of the SMNs occurred after relapse of HD and salvage therapy. The 4-year cumulative incidence rate of SMNs was 3.43% ± 1.2% in the dexrazoxane arm and 0.85% ± 0.6% in the arm without dexrazoxane (P = .06).

Our findings, specifically the absence of SMNs in the dexrazoxane-treated patients, serve as a note of caution in the interpretation and generalization of the results from Tebbi et al.²⁰ Their overall number of events was small, and the direct comparison of cumulative incidence of SMNs between the two groups was only of borderline statistical significance. Only after adjusting their results by standardizing against the general population did they reach a significant P value.

Several facts may explain the differences between our results and those of Tebbi et al.²⁰ First, the pediatric HD and childhood ALL patient populations differ with regard to underlying demographics, such as age at diagnosis. The median age at diagnosis in the DFCI cohort was 7 years compared with approximately 13 years in the HD cohort. Second, in our analysis, we treated relapse of leukemia as a competing event with SMNs, whereas Tebbi et al did not. We believe our method more accurately reflects the potential impact of dexrazoxane administered during initial therapy, because relapse therapy likely has an impact on the subsequent risk of SMNs. Of note, however, we are unaware of any SMNs occurring after relapse in our patients treated on Protocol 95-01.

In addition, although an excess of subsequent neoplasms has been reported in survivors of childhood ALL and HD, survivors of childhood and adolescent HD are recognized as having a higher incidence of SMNs.^26-31 Indeed, the cumulative incidences of SMNs after childhood ALL have been reported from 1.18% to 3.99% after 10 to 15 years, and 6.27% at 30 years of follow-up.^27,30,32 In childhood and adolescent HD, however, the cumulative incidence ranges from 3.82% to 18.7% at 10 to 15 years, and 26.3% at 30 years of follow-up.^26,29,33,34 In a report from the Childhood Cancer Survivor Study, SMNs of any type were independently associated with a childhood cancer diagnosis of HD in multivariate regression models adjusted for radiation exposure.³¹ In that cohort, onto which 1,815 HD patients and 4,581 leukemia patients were enrolled, 111 (6.1%) of HD patients reported an SMN, compared with only 64 (1.4%) of the leukemia patients. The difference in the distribution of SMNs between these two groups was statistically highly significant (P < .001).

In addition, treatment exposures differed between our population and that described in the study by Tebbi et al.²⁰ Of importance, etoposide was used in both arms of the pediatric HD study but not on Protocol 95-01. Treatment with etoposide has been associated with an increased risk of secondary AML/MDS.^35,36 Tebbi et al reported that the doses of etoposide (75 to 125 mg/m²/dose) used in the HD study have not been previously associated with an increased risk of secondary leukemia. However, others have reported such an association, even with relatively low doses, calling into question whether a safe dose of etoposide exists.³⁷ It is possible that the combined use of doxorubicin, dexrazoxane, and etoposide—all topoisomerase II inhibitors—led to a synergistic effect, as suggested by Tebbi et al, and contributed to the reported risk of SMN. However, dexrazoxane has been used for many years in combination with doxorubicin without reports of increased rates of SMNs. In addition, ionizing radiation was used in both our study and the study by Tebbi et al, although the radiation fields and radiation dose differed, which may have impacted the different rates on SMNs observed in the two studies.

It is interesting to note that both of the SMNs in our study were malignant melanomas. Both occurred outside of the radiation field and in patients who did not receive dexrazoxane. Melanoma is a relatively rare SMN reported in pediatric ALL patients. In a recent report from the St Jude Children's Research Hospital (Memphis, TN), only one melanoma was reported in more than 2,000 patients after a median follow-up of 18.7 years.³⁰ Similarly, in our own published experience of 1,600 patients treated for ALL on our protocols, no melanomas were observed as SMNs.³⁸ Given this, it is not clear if there is an association between ALL treatment and the development of melanoma, and longer follow-up will be needed to determine the incidence of melanoma in children with a history of ALL.

We note that our sample size is small and thus we have limited power to detect a difference in the incidence of SMNs between our two groups. We also acknowledge that our median follow-up was only 6.2 years, and that more SMNs may develop over time. However, median follow-up time in the study by Tebbi et al²⁰was similar to ours (5.8 years). In addition, no SMNs have been observed to date in our successor ALL study, Protocol 00-01, in which all HR patients (N = 212) received dexrazoxane (data not shown). Given the important role of dexrazoxane as a cardioprotectant and the lack of association with SMN in other reports, we recommend continued use of dexrazoxane in doxorubicin-containing pediatric ALL regimens. In addition, we recommend that the use of dexrazoxane be considered in other cancers in which pediatric patients receive relatively high doses of anthracyclines, and that patients receiving this cardioprotective agent be closely monitored for the development of late-occurring cardiac morbidity and SMNs. Finally, continued research regarding the incidence and cause of SMNs in HD patients is warranted before any conclusions regarding the use of dexrazoxane in this patient population can be made.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
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); Stephen E. Sallan, Enzon Pharmaceuticals (C); Elly V. Barry, Enzon Pharmaceuticals (C) Stock Ownership: None Honoraria: Stephen E. Sallan, Enzon Pharmaceuticals Research Funding: Steven E. Lipshultz, Pfizer, Novartis, Chiron; Stephen E. Sallan, Enzon Pharmaceuticals Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Conception and design: Donna S. Neuberg, Marshall A. Schorin, Steven E. Lipshultz, Stephen E. Sallan, Lewis B. Silverman

Financial support: Steven E. Lipshultz

Administrative support: Steven E. Lipshultz

Provision of study materials or patients: Barbara L. Asselin, Uma H. Athale, Luis A. Clavell, Eric C. Larsen, Albert Moghrabi, Yvan Samson, Marshall A. Schorin, Steven E. Lipshultz, Stephen E. Sallan

Collection and assembly of data: Suzanne E. Dahlberg, Donna S. Neuberg, Uma H. Athale, Steven E. Lipshultz, Stephen E. Sallan, Lewis B. Silverman

Data analysis and interpretation: Elly V. Barry, Lynda M. Vrooman, Suzanne E. Dahlberg, Donna S. Neuberg, Harvey J. Cohen, Steven E. Lipshultz, Stephen E. Sallan, Lewis B. Silverman

Manuscript writing: Elly V. Barry, Lynda M. Vrooman, Donna S. Neuberg, Uma H. Athale, Eric C. Larsen, Marshall A. Schorin, Steven E. Lipshultz, Stephen E. Sallan, Lewis B. Silverman

Final approval of manuscript: Elly V. Barry, Lynda M. Vrooman, Suzanne E. Dahlberg, Donna S. Neuberg, Barbara L. Asselin, Uma H. Athale, Luis A. Clavell, Eric C. Larsen, Albert Moghrabi, Yvan Samson, Marshall A. Schorin, Harvey J. Cohen, Steven E. Lipshultz, Stephen E. Sallan, Lewis B. Silverman

	NOTES

 
Supported in part by a grant from the National Institutes of Health (CA 68484).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
1. Blum RH, Carter SK: Adriamycin: A new anticancer drug with significant clinical activity. Ann Intern Med 80:249-259, 1974[Abstract/Free Full Text]

2. Sallan SE, Cammita BM, Cassady JR, et al: Intermittent combination chemotherapy with adriamycin for childhood acute lymphoblastic leukemia: Clinical results. Blood 51:425-433, 1978[Abstract/Free Full Text]

3. Jones SE, Grozea PN, Metz EN, et al: Superiority of adriamycin-containing combination chemotherapy in the treatment of diffuse lymphoma: A Southwest Oncology Group study. Cancer 43:417-425, 1979[CrossRef][Medline]

4. Bonadonna G, Zucali R, Monfardini S, et al: Combination chemotherapy of Hodgkin's disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer 36:252-259, 1975[CrossRef][Medline]

5. Cruz AB Jr, Thames EA Jr, Aust JB, et al: Combination chemotherapy for soft-tissue sarcomas: A phase III study. J Surg Oncol 11:313-323, 1979[Medline]

6. Ettinger LJ, Douglass HO Jr, Mindell ER, et al: Adjuvant adriamycin and cisplatin in newly diagnosed, nonmetastatic osteosarcoma of the extremity. J Clin Oncol 4:353-362, 1986[Abstract/Free Full Text]

7. Hoogstraten B, George SL, Samal B, et al: Combination chemotherapy and adriamycin in patients with advanced breast cancer: A Southwest Oncology Group study. Cancer 38:13-20, 1976[CrossRef][Medline]

8. Lefrak EA, Pitha J, Rosenheim S, et al: A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer 32:302-314, 1973[CrossRef][Medline]

9. Pai VB, Nahata MC: Cardiotoxicity of chemotherapeutic agents: Incidence, treatment and prevention. Drug Saf 22:263-302, 2000[CrossRef][Medline]

10. Sharpe HB, Field EO, Hellmann K: Mode of action of the cytostatic agent "ICRF 159". Nature 226:524-526, 1970[CrossRef][Medline]

11. Green MD: Rationale and strategy for prevention of anthracycline cardiotoxicity with the bisdioxopiperazine, ICRF-187. Pathol Biol (Paris) 35:49-53, 1987[Medline]

12. Hochster HS: Clinical pharmacology of dexrazoxane. Semin Oncol 25:37-42, 1998[Medline]

13. Thomas C, Vile GF, Winterbourn CC: The hydrolysis product of ICRF-187 promotes iron-catalysed hydroxyl radical production via the Fenton reaction. Biochem Pharmacol 45:1967-1972, 1993[CrossRef][Medline]

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

15. 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[Abstract/Free Full Text]

16. Lopez M, Vici P, Di Lauro K, et al: Randomized prospective clinical trial of high-dose epirubicin and dexrazoxane in patients with advanced breast cancer and soft tissue sarcomas. J Clin Oncol 16:86-92, 1998[Abstract/Free Full Text]

17. Speyer JL, Green MD, Kramer E, et al: Protective effect of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer. N Engl J Med 319:745-752, 1988[Abstract]

18. 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]

19. Lipshultz SE, Rifai N, Dalton VM, et al: The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med 351:145-153, 2004[Abstract/Free Full Text]

20. 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]

21. Smith M, Arthur D, Camitta B, et al: Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. J Clin Oncol 14:18-24, 1996[Abstract]

22. Pui CH, Sandlund JT, Pei D, et al: Improved outcome for children with acute lymphoblastic leukemia: Results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood 104:2690-2696, 2004[Abstract/Free Full Text]

23. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef]

24. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966[Medline]

25. Gray RJ: A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141-1154, 1988[CrossRef]

26. Bhatia S, Robison LL, Oberlin O, et al: Breast cancer and other second neoplasms after childhood Hodgkin's disease. N Engl J Med 334:745-751, 1996[Abstract/Free Full Text]

27. Löning L, Zimmermann M, Reiter A, et al: Secondary neoplasms subsequent to Berlin-Frankfurt-Munster therapy of acute lymphoblastic leukemia in childhood: Significantly lower risk without cranial radiotherapy. Blood 95:2770-2775, 2000[Abstract/Free Full Text]

28. Jenkinson HC, Hawkins MM, Stiller CA, et al: Long-term population-based risks of second malignant neoplasms after childhood cancer in Britain. Br J Cancer 91:1905-1910, 2004[CrossRef][Medline]

29. Green DM, Hyland A, Barcos MP, et al: Second malignant neoplasms after treatment for Hodgkin's disease in childhood or adolescence. J Clin Oncol 18:1492-1499, 2000[Abstract/Free Full Text]

30. Hijiya N, Hudson MM, Lensing S, et al: Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia. JAMA 297:1207-1215, 2007[Abstract/Free Full Text]

31. Neglia JP, Friedman DL, Yasui Y, et al: Second malignant neoplasms in five-year survivors of childhood cancer: Childhood cancer survivor study. J Natl Cancer Inst 93:618-629, 2001[Abstract/Free Full Text]

32. Bhatia S, Sather HN, Pabustan OB, et al: Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983. Blood 99:4257-4264, 2002[Abstract/Free Full Text]

33. Beaty O III, Hudson MM, Greenwald C, et al: Subsequent malignancies in children and adolescents after treatment for Hodgkin's disease. J Clin Oncol 13:603-609, 1995[Abstract/Free Full Text]

34. Kushner BH, Zauber A, Tan CT: Second malignancies after childhood Hodgkin's disease: The Memorial Sloan-Kettering Cancer Center experience. Cancer 62:1364-1370, 1988[CrossRef][Medline]

35. Pui CH, Ribeiro RC, Hancock ML, et al: Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med 325:1682-1687, 1991[Abstract]

36. Neglia JP, Meadows AT, Robison LL, et al: Second neoplasms after acute lymphoblastic leukemia in childhood. N Engl J Med 325:1330-1336, 1991[Abstract]

37. Stine KC, Saylors RL, Sawyer JR, et al: Secondary acute myelogenous leukemia following safe exposure to etoposide. J Clin Oncol 15:1583-1586, 1997[Abstract]

38. Kimball Dalton VM, Gelber RD, Li F, et al: Second malignancies in patients treated for childhood acute lymphoblastic leukemia. J Clin Oncol 16:2848-2853, 1998[Abstract]

Submitted May 10, 2007; accepted November 8, 2007.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				E. V. Barry, S. E. Lipshultz, and S. E. Sallan Anthracycline-induced Cardiotoxicity: Natural History, Risk Factors, and Prevention ASCO Educational Book, January 1, 2008; 2008(1): 448 - 453. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Barry, E. V. Articles by Silverman, L. B. Search for Related Content PubMed PubMed Citation Articles by Barry, E. V. Articles by Silverman, L. B. Social Bookmarking                            What's this?