Archives ofDisease in Childhood 1996;75:416-422

Early identification of anthracyclinecardiomyopathy: possibilities and implications

Frances A Bu'Lock, Martin G Mott, Anthony Oakhill, Robin P Martin

AbstractThe number of survivors of childhoodcancer affected by anthracycline cardio-myopathy is steadily increasing, despiteefforts to limit cardiotoxicity by doserestriction. Cardiac function was evalu-ated prospectively in 125 children duringtreatment to attempt to identify individualsusceptibilities to cardiotoxicity andhence any potential for treatment modifi-cation.

Left ventricular shortening fraction wasused as an index of cardiotoxicity. Short-ening fraction declined as cumulativeanthracycline dose increased, at an aver-age rate of 1% per 100 mg/m'. Six patients(5%) developed heart failure. Twenty fourpatients (19%) had abnormal shorteningfraction (200 mg/m'.

Patients at high risk ofrisk ofimportantanthracycline cardiotoxicity may be iden-tifiable early in treatment by regular andcareful monitoring of shortening fraction.However, frequent assessment is requiredand this has significant resource implica-tions.(Arch Dis Child 1996;75:416-422)

Keywords: cardiomyopathy, anthracycline, monitoring,echocardiography.

Bristol Royal Hospitalfor Sick Children,Department ofPaediatric CardiologyFA Bu'LockRP Martin

Department ofPaediatric OncologyMG MottA Oakhill

Correspondence to:Dr F A Bu'Lock,Department of PaediatricCardiology, Alder HeyChildren's Hospital, EatonRoad, Liverpool Ll 2 2AP.

Accepted 6 June 1996

The number of children and young adultsdeveloping cardiomyopathy after chemo-therapy for childhood malignancy is steadilyincreasing. Of the 1300 new cases of childhoodmalignancy in the UK each year, more thanhalf will receive cardiotoxic agents. For the last10-15 years, around 70% of patients have beenachieving long term survival,' thus >5000 sur-vivors are already at risk in the UK alone.The principal cardiotoxic agents used in

chemotherapy are the anthracyclines doxoru-bicin, daunorubicin, and epirubicin, whichcause a dose related, cumulative loss of cardiacmyocytes,2' probably mediated by toxic freeradicals generated by an intracellular iron-anthracycline complex.56 Cardiac irradiation,incurred during thoracic, craniospinal, or total

body radiotherapy will also cause significantcardiac damage, which is exacerbated byconcomitant anthracycline treatment." Highdose cyclophosphamide91' and mito-zantrone" 12 also cause cardiac injury.A number of ways to reduce cardiotoxicity

have been suggested but the use of less toxicanthracyclines,"'4 prolonged infusion sched-ules,5 16 or adjuvant cardioprotective agents,7 18although increasingly advocated, are not yet ofproved utility. Meanwhile, further attempts toimprove rates of cure using 'megatherapy' maysucceed only at the expense of an increase inthe incidence of anthracycline cardiomyopathy.

Clinical evidence of anthracyclinecardiotoxicity-congestive cardiac failure-isonly manifest very late. By this stage, histologi-cal myocardial damage is severe, all physiologi-cal compensatory mechanisms have failed, andthe prognosis is very poor indeed.'6.19.20 Histo-logical monitoring of subclinical cardiac dam-age is possible using electron microscopicassessment of serial endomyocardial biopsyspecimens,2 22 but this is both invasive andhighly resource intensive. Thus it is rarelyapplicable in clinical practice and measures ofleft ventricular function are generally used asless invasive surrogate markers of subclinicalmyocardial damage. Overall left ventricularejection function can be assessed using radio-nuclide angiography2 24 or echocardiogra-phy2526 and some groups have advocatedindices related to 'myocyte contractility', whichmay also be obtained echocardiographi-cally.2728 Measurement of transverse left ven-tricular systolic shortening fraction from the Mmode echocardiogram is probably the mostwidely used method. Although, like all non-invasive techniques, the use of shortening frac-tion does have some limitations, it has beenwell validated as a surrogate index of anthracy-cline cardiotoxicity by many groups.The majority of studies reporting the effects

of anthracyclines on left ventricular functionhave been cross sectional and have generallyconcentrated on status after treatment. How-ever, most report a relationship betweendecline in left ventricular function and increas-ing anthracycline dose, although with themarked individual variability in dose sensitivityalso noted in both clinical'29'0 and histopatho-logical" 2 studies. It is this individual variabil-ity that imposes limits on the efficacy ofuniform dose restriction in preventing anthra-cycline cardiomyopathy. However, if also mani-fest during treatment, it offers the possibilityfor early identification of susceptibility tocardiotoxicity to allow modification of subse-

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Early identification of anthracycline cardiomyopathy

quent treatment in the particularly 'atrisk'patient.The results of a detailed prospective study of

left ventricular function in children receivinganthracycline treatment were therefore exam-ined to determine whether the variation in sus-ceptibility to anthracycline cardiotoxicity couldbe detected using left ventricular shorteningfraction. If so, it was hoped to determine crite-ria that might be used for individual tailoringof antitumour treatment on the basis of bothoncological and cardiac status.

Subjects and methodsBetween August 1989 and July 1992, allchildren treated in our unit with chemotherapyregimens including anthracyclines participatedin a prospective cardiotoxicity study. Allpatients underwent detailed cardiovascular andechocardiographic examinations before first'on study' anthracycline treatment and shortlybefore each subsequent anthracycline treat-ment, as well as one month after the last treat-ment.

Height and weight were measured on eachoccasion and body surface area (BSA, in m')calculated from standard nomograms. Bloodpressure was recorded in mm Hg and anyabnormal cardiovascular symptoms or signswere noted. Blood haemoglobin concentrationwas >80 g/l on all occasions. All echocardio-graphic examinations were performed andanalysed by a single experienced operator(FAB).

Left ventricular systolic function was as-sessed by conventional steered M modeechocardiography from the parasternal longaxis view using a Hewlett Packard 77020ACultrasound scanner with simultaneous electro-cardiographic recording. Left ventricular di-astolic diameter (LVDD) and posterior walldiastolic thickness were measured at the pointof maximum diastolic posterior deflection ofthe posterior wall. Left ventricular systolicdiameter (LVDS) and posterior wall systolicthickness were measured at the point of maxi-mum anterior deflection of the posterior wall.The mean of measurements from four cardiaccycles were used and left ventricular shorten-ing fraction (%) was calculated from the meanleft ventricular dimensions as:

Shortening fraction = (LVDD - LVDS)x 100.LVDD

STUDY GROUPDuring the study period, 138 children under-went a total of 651 serial cardiovascular andechocardiographic examinations during an-thracycline chemotherapy for a variety ofhaematological and solid malignancies. An-thracyclines were administered by slow bolusinjection in increments of 35-100 mg/m' andfour patients also received cardiac irradiation.Where patients received additional cardiotoxicbut non-anthracycline treatment, subsequentexamination details have not been included.

Studies were stratified by cumulative anthra-cycline dose into nine groups: pretreatment,1-100 mg/M2, 101-200 mg/m', etc up to 700

mg/m', and >700 mg/m'. Equipotency for car-diotoxicity was assumed for all three types ofanthracycline (see below). Where more thanone study per patient fell within a single dosegroup, only the study performed at the highestdose was used for analysis.Data from 13 patients were completely

excluded by reason of death during inductiontreatment (n = 3), experimental cardioprotec-tion (n = 4), structural cardiac abnormalities(n = 2), technical difficulties (n = 1), or serialstudies only within the same 100 mg/m' doserange (n = 3).

After data stratification, a total of 451 serialechocardiograms performed during treatmentof 125 children for malignant disease wereused for analysis. There were 66 boys and 59girls, with BSAs between 0.34 and 2.08(median 0.8) m'. They were aged between 0.5and 20 (median 6.3) years at first study andreceived cumulative anthracycline doses be-tween 45 and 1150 (mean 320, median 270)mg/m'. Ninety two patients were studiedbefore receiving any anthracycline, 33 hadreceived prior anthracyclines and their dataseries started at doses between 70 and 600(median 150) mg/M2.

CONTROL DATAStudy data were compared with those obtainedfrom 137 healthy children and young adultsexamined by identical techniques, expressed asgroup median values for 0.2 m' BSA inter-vals.3334 Matched median normal control val-ues of all study parameters were determinedfor each patient on the basis of their BSA atfirst examination and were used for pairedcomparisons as described previously else-where."4

In our control studies fractional shorteningwas found to be independent of body size orage. The normal values were 38% for the 50thcentile, 35% for the 25th, and 34% for the1 0th. No normal subject had a shortening frac-tion 35% was consideredunequivocally normal, 30-34% 'borderline',and

Bu'Lock, Mott, OakhiU, Martin

Table 1 Changes in median values ofparameters of left ventricular systolic function with increasing anthracycline dose

Dose groupPatient (P) orcontrol (C) data 0 1 2 3 4 5 6 7 8 END

Dose (mg/m2) P 0 90 180 285 385 483 573 686 857 270Age (years) P 6.31 7.38 7.27 7.95 8.08 9.29 7.87 8.09 8.48 7.58

C 5.5 5.5 5.5 5.5 5.5 8.01 8.01 5.5 5.5 5.5BSA (m') P 0.81 0.85 0.85 0.94 0.90 0.99 0.98 0.94 1.0 0.88

C 0.78 0.78 0.78 0.78 0.78 1.02 1.02 0.78 0.78 0.78BPS (mmHg) P 110 110 100 100 105 100 100 85 90 100

C 95 95 95 95 95 95 95 95 95 95BPD (mm Hg) P 70 67 60 65 60 60 60 60 60 60

C 63 63 63 63 63 63 64 63 63 63LVDD (cm) P 3.64 3.66 3.73 3.80 3.82 3.88 3.78 3.81 4.26 3.80

C 3.63 3.63 3.63 3.63 3.63 3.91 3.91 3.63 3.63 3.63LVDS (cm) P 2.34 2.37 2.40 2.46 2.52 2.58 2.58 2.66 3.19 2.46

C 2.29 2.29 2.29 2.29 2.29 2.47 2.47 2.29 2.29 2.29SF(%) P 38 36 36 34 33 33 32 29 27 34

C 38 38 38 38 38 38 38 38 38 38PWD (cm) P 0.06 0.63 0.60 0.64 0.65 0.63 0.66 0.60 0.65 0.62

C 0.56 0.56 0.56 0.56 0.56 0.60 0.60 0.56 0.56 0.56PWS (cm) P 0.97 1.0 0.95 1.0 0.97 1.05 .98 0.89 0.92 0.96

C 0.92 0.92 0.92 0.92 0.92 1.03 1.03 0.92 0.92 0.92% withSF

Early identification of anthracycline cardiomyopathy

0.0008 0.0003

T ENDSF.-AI>30%

301-4l0 401-1u0

Figure 2 Shows median and interquartile range (error bars) values for left ventricularshorteningfraction with increasing anthracycline dose, subdivided on the basis ofend oftreatment shortening fraction (ENDSF 30%, n = 101, and ENDSF

Bu'Lock, Mott, Oakhill, Martin

first studied before receiving any anthracycline,11 had end of treatment shortening fraction

Early identification of anthracycline cardiomyopathy 421

cumulative anthracycline dose and left ven-tricular shortening fraction. The marked indi-vidual variability in the rate of fall of fractionalshortening with increasing anthracycline doseis consistent with other studies.'29-32 It is there-fore highly noteworthy that each individual'sbehaviour appears to be relatively consistentthroughout treatment and has a clear relation-ship to the functional status at the end ofanthracycline treatment. Thus, the use of acombination of measurement of the rate of fallof shortening fraction and of individual abso-lute values of fractional shortening at lowanthracycline doses, should allow identifica-tion of patients particularly susceptible toanthracycline cardiotoxicity early on in treat-ment. However, these results are drawn from aretrospective analysis of prospectively acquireddata and would benefit from further prospec-tive validation.The most disturbing aspects of anthracy-

cline induced cardiac damage are the long termimpairment of cardiac function and the in-creasing incidence of late decompensationwhich have only recently become appar-ent.283437 It appears that after an initial 'honey-moon period',"839 in which surviving myocytesare able to compensate for the acute myocyteloss by hypertrophic changes (fractional short-ening may even return to near normal values),there is a continuing myocardial attenuation,probably due both to failure of further myocytegrowth and gradual loss of 'overworked'residual myocytes. Our own studies and thoseof other groups have now demonstrated thatmyocardial thickness and function deterioratewith time after anthracycline treatment,283437with more than 40% of patients showingsignificant abnormalities of cardiac function

115 years after anthracycline treatment.40Since Steinherz et al have also demonstrated aclear relationship between end of treatmentcardiac status/shortening fraction and likeli-hood of late decompensation"37 the ability topredict likely functional outcome early in treat-ment becomes even more crucial.There has been considerable discussion

about both the value and timing of monitoringfor anthracycline cardiotoxicity.2'26130 41 Theguidelines suggested by the Children's CancerStudy Group were based on a large experienceat the Memorial Sloan Kettering CancerCenter and on previously reported studies.42These guidelines have been criticised byLipshultz et al,4' as being both unproved and ashaving potential negative consequences forantitumour treatment. The present 'on treat-ment' study is the first to identify a number ofpotential pointers to each individual's suscepti-bility to anthracycline cardiotoxicity, which canbe applied throughout treatment. It is not sug-gested that these criteria be used to define rigidlimits for cessation of anthracycline treatment,but rather to provide the basis for informedconsideration of the risks and benefits ofcontinuation of anthracycline treatment in anygiven oncological situation. Overt cardiacfailure is an absolute contraindication tocontinuation of anthracycline treatment; lesserdegrees of myocardial dysfunction or increased

sensitivity to cardiotoxicity may warrant eitherdose reduction or early cessation of treatment.Where the risk that treatment modificationmay significantly jeopardise antitumour suc-cess is substantial, an informed decision tocontinue anthracyclines may be justified. Inless susceptible patients, the beneficial use ofhigher than usual doses of anthracycline maybe facilitated and the standard recommendedmaximum doses perhaps need no longer apply.As cardioprotective agents become avail-able,"'5 identification of those patients mostsusceptible to cardiotoxicity might provide arational basis for their selective use.

ConclusionsRegular monitoring of left ventricular shorten-ing fraction early during anthracycline treat-ment can identify those patients at higher riskof subsequent cardiotoxicity. Patients withfractional shortening 2-3 absolute % per 100 mg/m'would appear to be at increased risk of signifi-cant cardiotoxicity. Modification of treatmentshould be considered for these patients in thelight of each individual's tumour status.The echocardiographic determination of

individual susceptibility to anthracycline car-diotoxicity requires pretreatment and frequentlow dose studies, and a meticulous anduniform echocardiographic technique. Suchmonitoring has significant resource implica-tions. Further prospective studies of theclinical value and cost effectiveness of on treat-ment monitoring are now indicated, using thecriteria determined in this study.

FAB was supported by the Cancer Research Campaign, MGMis professor ofpaediatric oncology and is supported by the Can-cer and Leukaemia in Childhood Trust.

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