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Anthracyclines: Cardiotoxicity and Its Prevention

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Anthracyclines: Cardiotoxicity and Its Prevention Archives ofDisease in Childhood 1994; 71: 457-462 457 CURRENT TOPIC Arch Dis Child: first published as 10.1136/adc.71.5.457 on 1 November 1994. Downloaded from Anthracyclines: cardiotoxicity and its prevention J P Hale, I J Lewis The anthracycline antibiotics have now been in administration of anthracyclines was first use in curative chemotherapy protocols for recognised when patients presented clinically over two decades. They are highly active with symptoms of congestive heart failure5 against a wide range of haemopoietic and solid within six months of their last dose of anthra- tumours in children and adults. Unfortunately, cycline. The outcome was often fatal and their antineoplastic use is limited by significant necropsy showed the cytoplasmic vacuolisation and irreversible cardiotoxicity, the full extent and myocyte necrosis since recognised as of which continues to emerge. As more child- typical of anthracycline damage.5 This review ren become long term survivors of cancer, the will focus on late toxicity. relative impact of anthracycline induced cardiac damage has increased but, despite an understanding of the pathogenesis, consensus Risk factors and incidence strategies for detection and prevention have The prime factor determining the risk of devel- not been established. oping anthracycline induced cardiomyopathy is the cumulative dose of anthracycline received.5 Estimates of the incidence of Historical perspective cardiomyopathy vary depending on the end Daunorubicin, the first anthracycline anti- point being used. Von Hoff and coworkers' biotic to be used, was isolated in Italy in 1963 large series from the 1970s7 8 using early from cultures of Streptomyces peucetius.I In clinically overt congestive cardiac failure as phase II trials it showed activity against acute the end point estimated the incidence of lymphoblastic leukaemia and acute myeloid daunorubicin induced cardiomyopathy to be leukaemia. Doxorubicin, isolated shortly 2% at 600 mg/M2 and 17% at 1050 mg/M2. afterwards,2 showed demonstrable The for doxorubicin were activity equivalent figures http://adc.bmj.com/ against a wider range of tumours in children, 7% at 550 mg/mi2 and 18% at 700 mg/M2. The including soft tissue and bone sarcomas, rapid increase in toxicity above 550 mg/M2 led Wilms' tumour and lymphomas, as well as to this being used as a limiting dose for the two lymphoblastic and myeloid leukaemia. Early drugs. phase I trials involved patients with wide- The risk of cardiotoxicity is potentiated by spread disease and reports of cardiotoxicity3 mediastinal radiation,9 advancing age,8 9 and could only uncertainly attribute toxicity to the pre-existing cardiac disease or hypertension,8 drug rather than the disease. With increasing although the effects of advancing age and on September 25, 2021 by guest. Protected copyright. use of anthracyclines, however, it became cardiac disease may not be independent. The apparent that daunorubicin and doxorubicin effect of young age at the time of treatment is were directly cardiotoxic in children4 and less certain. Von Hoff and coworkers7 8 found adults.5 that children younger than 15 years had a Originally cardiac toxicity was described higher risk of developing cardiac failure than as being acute or subacute and was seen adults with daunorubicin and doxorubicin. during or immediately after one dose or Within a paediatric group Lipshultz et al course of anthracycline. Additionally, late or found an increased risk for children treated chronic toxicity occurred after prolonged under 4 years of age of developing subclinical administration of anthracycline.6 Acute cardiomyopathy with long follow up,10 but toxicity was seen as transient changes on this was not confirmed by Steinherz et al.11 electrocardiograms, typically ST and T Although early studies found no effect of wave flattening, and arrhythmias, typically gender, it has been suggested that girls may be sinus tachycardia.5 7 These changes usually at increased risk of cardiotoxicity. 12 reverted to normal, were independent of dose, The increasing numbers of long term and were mainly seen in adults. The sub- survivors and the availability of routine echo- Regional Centre for acute toxicity was manifest as a pericarditis- cardiography in the late 1 970s meant that Paediatric Oncology, myocarditis syndrome or as acute left reports began to appear of cardiac decompen- St James's University ventricular failure6 and was particularly seen sation occurring for the first time 10 years after Hospital, Beckett in early trials of anthracyclines in when Street, Leeds LS9 7TF adults initial treatment13 and of subclinical cardio- J P Hale scheduling led to doses as high as 160 mg/m2 myopathy.14 Steinherz et al assessed cardiac I J Lewis being delivered over times as short as four function by measuring fractional shortening in Correspondence to: days. patients treated in childhood up to 20 years Dr Lewis. Late cardiotoxicity developing after repeated from completing treatment and found an 458 Hale, Lewis overall 23% incidence of abnormal cardiac method of cardiac assessment which detects function."1 This increased to 63% in the early cardiac damage, is easily performed, and Arch Dis Child: first published as 10.1136/adc.71.5.457 on 1 November 1994. Downloaded from subgroup who had received more than 500 has predictive power. mg/m2 and had been followed up for more The electrocardiogram was the earliest than 10 years. Late decompensation as a method used for monitoring toxicity, but the result of pregnancy or weight training was transient changes seen with acute toxicity had well recognised. Using more sensitive load little predictive value for the development of independent echocardiographic measures of cardiomyopathy.7 Schwartz et al suggest that cardiac function, Lipshultz et al found an the prolongation of the QT interval (QTc) is a overall incidence of 57% abnormalities,10 useful screening test for early cardiac damage with up to 15 years' follow up. The full extent when echocardiography remains normal,'9 but of the problem and the functional significance its relation with clinical outcome is unproved. of asymptomatic abnormalities is as yet In Stanford, Billingham and coworkers unclear. pioneered the development of taking right ventricular endomyocardial biopsy samples and a biopsy scoring system which, in the Pathology hands of an experienced pathologist, correlates Electron microscopic examination of endo- well and linearly with the cumulative anthra- myocardial biopsy samples from patients cycline dose.9 Using endomyocardial biopsy treated with anthracyclines shows myofibril samples it is possible to predict the rate of loss, swelling ofthe sarcoplasmic reticulum and progression ofdamage for any individual,20 but mitochondria, cytoplasmic vacuolisation, and there is an associated morbidity and therefore widespread damage with necrosis ofmyocytes.9 there are concerns about the invasiveness of These changes may be focal or diffuse. repeated treating in children.2' The number of myocytes present in the adult Echocardiographic measurement of frac- heart is established by the age of 6 months. tional shortening and ejection fraction as Myocytes lost by necrosis are not replaced, but indicators of left ventricular systolic function is the remaining myocytes increase in size to com- the most widely used method of assessing pensate. There is also an increase in the amount cardiotoxicity, but is complicated by the ability of interstitial tissue and fibrosis. The changes of the myocardium to compensate for early seen in children and adults are the same. damage. The sensitivity of systolic echocardi- For children sustaining anthracycline ography can be improved by exercise testing22 cardiotoxicity, myocyte loss means the left when failure of the fractional shortening to ventricular wall becomes relatively thin and increase in response to exertion may indicate particularly fails to keep pace with pubertal or early cardiomyopathy. Similar, asympto- growth hormone induced growth spurts,1013 matic cardiomyopathy can be unmasked by occasionally causing subclinical damage to echocardiography during low dose dobut- become clinically overt at this time. amine infusions at a time when other physio- logical studies are normal.23 http://adc.bmj.com/ Fractional shortening is affected by variables Mechanism ofdamage such as anaemia, fever, and volume infusions At the current level of understanding the that influence left ventricular loading condi- mechanisms by which anthracyclines produce tions and interfere with the relation between antitumour activity and cardiotoxicity appear fractional shortening and contractility. Atten- different. The antitumour activity of anthra- tion has focused on load independent echo- cyclines seems to be exerted by intercalation in cardiographic measures of systolic function on September 25, 2021 by guest. Protected copyright. double stranded DNA and stabilisation of the such as end systolic wall stress and the stress- topoisomerase II-DNA complex, which is an velocity index. These are sensitive indicators of essential stage of DNA replication, resulting cardiac dysfunction,'024 but are complicated in DNA strand breaks.15 In contrast, the to measure and require cooperation in young cardiotoxicity of anthracyclines is almost children. Follow up studies using these certainly mediated by free radical damage measures10 show increasing end systolic wall which is not involved in the antitumour effect. stress with increasing anthracycline dose. This Anthracyclines,
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