Pediatr Blood Cancer 2005;44:584–588

REVIEWDexrazoxane for the Prevention of Cardiomyopathy in

Anthracycline Treated Pediatric Cancer Patients

Barry Anderson, MD, PhD*

INTRODUCTION

Anthracyclines have played a major role in combina-tion chemotherapeutic regimens for a wide variety ofchildhood cancers. A review of current clinical trialsunderway by the Children’s Oncology Group (COG)demonstrates that anthracyclines, primarily doxorubicin,but also daunomycin, are included in the treatment ofacute lymphoblastic leukemia (ALL), acute myeloblasticleukemia (AML), non-Hodgkins lymphoma (NHL),Hodgkins disease (HD), neuroblastoma, Wilms tumor,osteosarcoma (OS), and Ewing sarcoma. As the cumula-tive dose of anthracycline, especially doses >550 mg/m2

[1], is a major determinant of early cardiotoxic severity inchildren, it should be noted that the cumulative anthracy-cline dose inmany current regimens remains�300mg/m2

for children with T cell leukemia, AML, high-risk neuro-blastoma, advancedHD, hepatoblastoma, NHL, and Ewingssarcoma. Osteosarcoma regimens treat to a cumulativedoxorubicin dose of 450 mg/m2. This ongoing use ofanthracycline gains importance as reports have demon-strated that late cardiotoxicity, developing a year or moreafter completion of therapy, occurs among a significantproportion of children treated with anthracycline at thesecumulative doses [2,3] and even at doses less than 300mg/m2 [4,5]. Although pediatric oncologists have sought todiminish the toxic effects of anthracyclines byminimizingthe dose used in combined chemotherapy, relatively highdoses of anthracyclines remain essential to the clinicaleffectiveness of many contemporary treatment regimens.

Oncologists have also attempted to diminish anthracy-cline related cardiotoxicity by dividing or prolonging theadministration schedule of the drug. The administration ofdoxorubicin in consecutive divided daily doses comparedwith a single dose did not significantly reduce the likeli-

hood of cardiotoxicity in children receiving a mean of341 mg/m2 cumulative doxorubicin during treatment [6].The use of prolonged anthracycline infusions of 6–96 hrhas been promoted to diminish acute cardiotoxicity,purportedly by lowering the peak drug concentrationwhile maintaining the total drug dose, although the moreprolonged infusion times are associated with increasedmucositis. Recent follow-up reports on prolonged infusiontrials have not found significant differences in late cardio-toxicity between bolus or continuous infusion (48 hr)doxorubicin (30 mg/m2 dose; 360 mg/m2 cumulativedose) in high-risk ALL [7], or in bolus versus >24 hranthracycline infusion (median 365 mg/m2 cumulativeanthracycline dose) in children with multiple cancerdiagnoses [8], or 6-hr infusion compared with bolusdelivery daunorubicin (cumulative 180 mg/m2 dose)among children with ALL [9].

The lack of demonstrable benefit frommodifications inanthracycline delivery increases the importance of pre-ventative approaches to reducing anthracycline-inducedcardiotoxicity. Anthracycline cardiac damage presumablyresults from the formation of anthracycline–iron com-plexes within myocardial cells [10]. These complexescatalyze the formation of hydroxyl radicals that causeoxidative damage to the cells. Dexrazoxane is a chelating

Anthracyclines play a major role in chemo-therapeutic regimens for a variety of childhoodcancers, but produce dose-related cardiotoxi-city. Dexrazoxane, a chelating agent that bindsiron intracellularly, has been cautiously in-cluded in anthracycline-based regimens. Ourunderstanding of anthracycline and dexra-zoxane pharmacokinetics in children is verylimited. In addition, the administration schedule

used for adults (bolus dexrazoxane prior to bolusanthracycline) may not be the best to attain bothshort- and long-term cardioprotection. Dexra-zoxane could diminish the anti-tumor activity ofand/or increase toxicities from anthracyclines.Pediatric oncologists must be assured this inter-vention does not diminish the success in curingchildren with cancer. Pediatr Blood Cancer2005;44:584–588. � 2005 Wiley-Liss, Inc.

Key words: anthracycline; cardiotoxicity; dexrazoxane

� 2005 Wiley-Liss, Inc.DOI 10.1002/pbc.20358

——————Clinical Investigations Branch, Pediatric Section, Cancer Therapy

Evaluation Program, National Cancer Institute, Rockville, Maryland

*Correspondence to: Barry Anderson, Clinical Investigations Branch,

Pediatric Section, Cancer Therapy Evaluation Program, National

Cancer Institute, 6130 Executive Blvd., Executive Plaza North,

Rockville, MD 20852. E-mail: andersonb@ctep.nci.nih.gov

Received 17 December 2004; Accepted 17 December 2004

agent that binds iron intracellularly and is thought to bindup myocardial cell iron as well as extract iron from theanthracycline–iron complexes [11]. Dexrazoxane hasbeen developed as a cardioprotectant agent over the past15 years, although it was originally investigated as ananti-neoplastic agent given its topoisomerase II inhibitoryactivity. This cardioprotectant has been cautiously in-cluded in active, anthracycline-based regimens due toconcerns that the dexrazoxane could diminish the anti-tumor activity of the anthracyclines or increase otherchemotherapy-related toxicities.

Use of Dexrazoxane in Adults

Large randomized trials of dexrazoxane have beenconducted in adults, especially among women with breastcancer, a disease for which doxorubicin has been centralto chemotherapy. Two multi-center clinical studies inwomen with advanced breast cancer have had the greatestinfluence on the use of dexrazoxane in this cancerpopulation [12,13]. Five hundred thirty-four women weretreated with 5-fluorouracil, doxorubicin (50 mg/m2/course), and cyclophosphamide (FDC) and were rando-mized to receive dexrazoxane (500 mg/m2) or placeboprior to each dose of doxorubicin. Serial MUGA scanswere performed to monitor patients for subclinicalcardiotoxicity. Congestive heart failure occurred in 8%of the placebo patients, but in only 1% of patientsreceiving dexrazoxane (P<.001). Clinical cardiac eventsdeveloped in 31% of the placebo patients and only 14% ofthe dexrazoxane group. As the study involved repeatingFDCcourses until an event occurred, it is important to notethat at a cumulative doxorubicin dose of 800 mg/m2

approximately 20% of the placebo versus 80% of thedexrazoxane patients remained free of a cardiac event inthe larger of these two studies. Importantly, the largerof these two studies reported a significant difference inthe tumor response rate (47% vs. 61%) among womenreceiving dexrazoxane versus placebo, although it appearsthat this difference resulted from an abnormally highresponse rate in the placebo group. The parallel studydemonstrated response rates similar to that in the dexra-zoxane arm of the larger study, and there was no dif-ference found in response rate between the dexrazoxaneor placebo arms, 54% versus 49%, respectively. However,as described later, the report of a difference in tumorresponse among dexrazoxane patients in this randomizedstudy has had significant impact on the use of dexrazoxanein adults [14].

Due to the significant cardioprotection noted duringthese two studies, the protocols were amended for sub-sequent accruals such that all patients were initiallyrandomized to dexrazoxane or placebo, but after acumulative doxorubicin dose of 300 mg/m2 (six courses)all patients with evidence of benefit from FDC treatment

received open-label dexrazoxane with subsequent coursesof FDC. The risk of experiencing a cardiac event was overthree-times greater and the risk of having congestive hearfailure was over 13-times greater at any given cumulativedose of doxorubicin for patients in the placebo groupthan for those patients receiving dexrazoxane. Further, thewomen who received dexrazoxane with their seventhcourse of chemotherapy had a substantial increase insurvival (882 vs. 460 days, P< 0.001), apparently due tothe increased number of FDC cycles tolerated by thesepatients. Thus, the second phase of this study indicatedthat cardiac benefit also occurred when dexrazoxaneuse was delayed until after 300 mg/m2 of doxorubicinexposure.

The 2002 updated recommendations by the AmericanSociety of Clinical Oncology Expert Panel for the useof dexrazoxane limits the drugs use to patients withmetastatic breast cancer who have received more than300 mg/m2 of doxorubicin [15]. The Panel cites Swainet al. [13] regarding the beneficial decrease in cardiotoxi-city that is also seen when dexrazoxane use is started after300 mg/m2 cumulative doxorubicin as the rationale toavoid the increased expense and possible increased toxi-city of using dexrazoxane at the initiation of doxorubicin-based chemotherapy. The use of dexrazoxane in theadjuvant setting is recommended only in the context of aclinical trial, due to the lack of randomized, controlledstudies demonstrating a benefit of dexrazoxane use duringadjuvant chemotherapy for metastatic or non-metastaticbreast cancer. The recommendations continue to expresscaution in the use of dexrazoxane for other diseases inwhich doxorubicin-based therapy has been shown toimprove survival, due to the reported decrease in tumorresponse rate in the Swain study [12].

Reports on the Use of Dexrazoxane inChildhood Cancer

Contemporary data on the use of dexrazoxane inchildren receiving anthracyclines as part of a clinical trialis just beginning to develop. Several early reports ofsmall numbers of children with recurrent [16] or newlydiagnosed [17] malignancy receiving dexrazoxane withanthracycline-based salvage or adjuvant chemotherapy,respectively, compared the cardiologic outcomes withsimilar patients treated contemporaneously without dex-razoxane. The dexrazoxane-treated children demonstratedno significant toxicity with dexrazoxane administrationand developed no evidence of early clinical cardiotoxicity,while the children treated without dexrazoxane had apoorer cardiologic outcome in general. However, thepatients in both studies represented an inhomogeneousgroup of cancer diagnoses treated with a variety ofchemotherapy regimens and various cumulative anthra-cycline doses.

Dexrazoxane Prevention of Pediatric Cardiotoxicity 585

The Pediatric Oncology Branch conducted an earlyrandomized study in newly diagnosed sarcoma patientsfrom 1989 to 1992 in which patients received vincristine/cyclophosphamide/adriamycin alternating with ifosfa-mide/etoposide every 21 days for 18 cycles and wererandomized to receive dexrazoxane or no additionalintervention prior to doxorubicin infusion [18]. Eighteenpatients received chemotherapy alone and 23 patientsreceived chemotherapy with dexrazoxane and all patientswere followed with serial MUGA scans to monitor forchanges in left-ventricular ejection fraction. Twelve of the20 evaluable dexrazoxane treated patients reached thetargeted 410 mg/m2 cumulative adriamycin dose com-pared to 8 of 18 patients treated without dexrazoxane.Importantly, the left-ventricular ejection fraction amongpatients who reached the 410 mg/m2 cumulative dose was54% versus 44% (P¼ 0.03) in the dexrazoxane treatedversus chemotherapy alone arm. Subclinical cardiotoxi-city was demonstrated in 67% of the patients treated onthe chemotherapy only arm, while a significantly lowernumber of dexrazoxane treated patients developed de-tectable cardiac dysfunction (22%, P< 0.01). The tumorresponse to the chemotherapy, determined after fourcycles of chemotherapy, was comparable, 80% versus81%, with or without dexrazoxane, respectively. Thus, theauthors concluded that dexrazoxane was beneficial indecreasing the incidence of short-term subclinical cardi-otoxicity in childhood sarcoma patients receiving doxo-rubicin up to a dose of 410mg/m2 and no interferencewiththe anti-tumor effectiveness of the chemotherapy regimenwas found.

Four clinical studies evaluating a role for dexrazoxanehave been completed in the recent past by the PediatricOncology Group (POG). Over 500 children with T cellALL or lymphoblastic non-Hodgkin leukemia (POG9404) were randomized to receive chemotherapy plusdexrazoxane or no additional agent using a combinationchemotherapy regimen that included doxorubicin to acumulative doxorubicin dose of 360 mg/m2 during in-duction and consolidation treatment. The cardiac effect ofdexrazoxane was monitored by echocardiogram at thecompletion of doxorubicin therapy and then 1 year aftercompletion of all therapy. No cardiac outcome data areyet available, but most patients should have undergonethe 1-year off study cardiac evaluation recently, so resultsare anticipated soon.

Two randomized studies in low stage (POG 9426) andadvanced (POG 9425) Hodgkin disease used dexrazoxanein response-based chemotherapy regimens that incorpo-rated a variety of cumulative doxorubicin doses. Childrenwith low stage HD received doxorubicin/bleomycin/vincristine/etoposide (DBVE)� dexrazoxane, and thecumulative doxorubicin dose was only 100 or 200 mg/m2.Advanced stage disease was treated with DBVE pluscyclophosphamide and prednisone (DBVE-PC) with

randomization to dexrazoxane or no additional agent withthe cumulative doxorubicin dose of 180 or 300 mg/m2.Patients in both studies underwent serum cardiac troponinT collection before and after doxorubicin treatment asa means to evaluate acute myocardiotoxicity. Thechildren with advanced disease also had echocardiogramsperformed during and 1 year following completion oftreatment. Evidence of dexrazoxane influence on anti-tumor effectiveness was assessed by monitoring thecomplete response rate during the study conduct andevent-free survival will be an important comparator aswell. An early report from these studies [19] indicates thatchildren who received dexrazoxane had a significantincrease in the incidence of grades 3 and 4 hematologicaltoxicity. The investigators noted an increased number ofreported cases of typhlitis among children treated withDBVE-PC with dexrazoxane compared with chemother-apy alone. Finally, the early reports also indicate a greaterincidence of secondary malignancy among patients re-ceiving dexrazoxane with either chemotherapy regimencompared with children receiving chemotherapy alone,although the overall number of secondary malignanciesremains small. Follow-up reports on the effect of dexra-zoxane on acute cardiotoxicity, as monitored by cardiactroponin T, and late cardiotoxicity will be particularlyinteresting for these two studies given the range of cumu-lative doxorubicin doses received.

Dexrazoxane was also recently used for all patientstreated in a series of pilot studies for non-metastatic osteo-sarcoma (POG 9754). Patients received standard combi-nation chemotherapy for osteosarcoma (doxorubicin,high-dose methotrexate, cisplatin) in pilot 1 and ifosfa-mide was added to the regimen in pilot 2. All patientsreceived dexrazoxane prior to doxorubicin administration.Tumor response was evaluated at the time of tumorresection (scheduled atweek 12) and patientswhose tumordemonstrated a standard response (<98% tumor necrosis)were scheduled to receive a total doxorubicin dose of600 mg/m2, while patients with a good tumor response(>98% tumor necrosis) received the standard 450 mg/m2

cumulative doxorubicin. Investigatorsmonitored the tumorresponse for these patients to judge any influence thedexrazoxane may have on early response to chemother-apy; however, there was no adverse effect on the deliveryof the pre-operative chemotherapy and the percentageof patients demonstrating a good tumor response atsurgery (30%) was as expected from historical data [20].Importantly, this single arm study demonstrates that ahigher cumulative dose of doxorubicin (600 mg/m2) canbe delivered without apparent acute cardiotoxicity,although whether dexrazoxane will diminish the latecardiac effects of the combination chemotherapy withelevated total anthracycline dose awaits further follow-up.

An important report was recently published regardingthe Dana–Farber Cancer Institute childhood ALL con-

586 Anderson

sortium protocol 95-001 [21] in which 206 childrenless than 18 years of age with high-risk ALL receivedmulti-agent chemotherapy and central nervous systemradiotherapy and were randomly assigned to receivedexrazoxane prior to the administration of doxorubicin(30 mg/m2/dose), which was given during remissioninduction and during the subsequent 9 months consolida-tion phase, or chemotherapy without dexrazoxane. Thetotal doxorubicin dosewas 300mg/m2. Cardiac troponinTwas measured in serum collected at diagnosis, followingdoxorubicin doses and then at the completion of therapy.Echocardiograms were also performed in a subgroup ofpatients. The investigators found that a significantly lowernumber of patients receiving dexrazoxane with doxo-rubicin demonstrated any elevations in cardiac troponin T(21% vs. 50%, P< 0.001) and these same patients haddecreased incidence of extreme or repeated cardiac troponinT elevations throughout the treatment course. Given theemphasis in other studies to monitor subclinical cardiactoxicity by use of cardiac echocardiograms, it is interest-ing to note that this study found no significant differencesin the mean left ventricular dimension, fractional short-ening, or contractility among children who did and did notreceive dexrazoxane with doxorubicin. All children hadsignificant depression of cardiac fractional shorteningduring and following doxorubicin treatment. Importantly,the event-free survival at 2.5 years was 83% in bothtreatment groups (P¼ 0.87). The effects that dexrazoxanemay have had on late cardiotoxicity and long-term eventfree survival awaits further follow-up.

While the data from the recent POG studies regardingthe usefulness of dexrazoxane will be helpful in deter-mining a role for this agent for a variety of cumulativedoxorubicin doses used in combination chemotherapy forHodgkin disease, T-cell leukemia and osteosarcoma, it isconcerning that the age of the patients for these clinicalstudies will be, by virtue of the epidemiology of eachparticular cancer, skewed towards pre-teenage, and ado-lescent patients. The small randomized study of dexra-zoxane performed at the NCI Pediatric Oncology Branchhad a median patient age of 18.5 years. The study con-ducted at DFCI in high-risk ALL had a median age atdiagnosis of 7.5 years. Studies have demonstrated thatchildren treated with anthracyclines at a younger age havea greater likelihood of developing significant cardiotoxi-city [1,22]. Considering the ages of the patients treatedwith dexrazoxane in the available studies, the true impactof dexrazoxane use in the pediatric population mostvulnerable to anthracycline cardiac damage may not beappreciated from the clinical trials that have been per-formed to date.

Additionally, several issues may hinder our ability togain maximal benefit from the use of dexrazoxane inchildren; these include the limits on our understanding ofanthracycline pharmacokinetics in children and the very

limited pharmacokinetic information for dexrazoxane inyounger patients [23]. Secondly, it is not clear that theadministration schedule utilized in adults, bolus dexra-zoxane prior to bolus anthracycline, is the ideal approachto attain both short- and long-termcardioprotection. In thisregard, research into the pharmacokinetics of anthracy-cline cardiotoxicity that might delineate the timelinefor the anthracycline damaging process after an anthra-cycline dose is given could prove very important tosuccessfully implementing dexrazoxane cardioprotectionin children.

Refinement of dexrazoxane use in childhood cancerregimens awaits, however, the vital late cardiotoxicityfollow-up data from the recent clinical studies to establishthat the addition of this drug is truly beneficial. Pediatriconcologists must be assured that the addition of thissupportive intervention does not diminish the success incuring childrenwith these cancers and that the preliminaryreports of increased hematologic toxicity and increasedsecondarymalignancy associated with dexrazoxane use inyoung patients does not negate any cardiac benefit.

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