5.1 Cardiac problems

Evidence on the cardiotoxic effects of chemotherapy and/or radiation therapy in the treatment of children with cancer comes from retrospective cohort studies, which cover a range of ages and regimens and which include differing drugs and radiation.^{148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160} Most of these studies are historical and employ different schedules and doses from those currently in use. Given these limitations, the studies suggest that there is no evidence of an increased risk of coronary artery disease if chemotherapy alone is used. Evidence level 2++,2+,3

There is robust evidence that anthracyclines can cause congestive cardiac failure.^{161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182} The main anthracyclines reported in the literature are daunorubicin and doxorubicin, with some studies addressing the cardiotoxicity of other anthracyclines, namely mitoxantrone, epirubicin, idarubicin^{183, 184} and amsacrine.¹⁸⁵ There is probably no safe dose,¹⁸² but the higher the accumulated dose, the greater the risk.^{171, 174} Adverse cardiac effects increase over time. Higher doses of anthracyclines are associated with an increased incidence of abnormal echocardiograms. Younger age at treatment and female gender are independent risk factors in several studies.^{165, 171, 172} Evidence level 2++,2+,3

Healthcare professionals should be aware that effective doses of anthracyclines for the treatment of childhood cancer may cause congestive cardiac failure later in life. These problems should be assessed during regular review.

A single preliminary study reported that the cardioprotective agent ICRF-187 reduced the risk of developing short term subclinical cardiotoxicity in paediatric sarcoma patients who received up to 410 mg/m2 of doxorubicin. Further clinical trials with larger numbers of patients are required to determine if the short term cardioprotection afforded by ICRF-187 will reduce the incidence of late cardiac complications in long term survivors of childhood cancer.¹⁸⁶ Evidence level 1-

Liposomal daunorubicin*, daunoxome, is currently under evaluation for both efficacy and reduced cardiotoxicity. There is insufficient evidence at this time to make recommendations.

Although there is some evidence to support prolonged anthracycline infusions in adults,¹⁶⁵ a recent RCT has shown no cardioprotective effect from 48-hour infusions in children. Continuous doxorubicin infusion over 48 hours for childhood leukaemia did not appear to offer a cardioprotective advantage over bolus infusion although differences may emerge with longer follow up.¹⁸⁷ Evidence level 1-

5.1.1 RADIATION THERAPY AND CARDIAC PROBLEMS

Mediastinal irradiation as treatment for Hodgkin’s disease increases the incidence of coronary artery disease and myocardial infarction.¹⁴⁸ The risk increases with high mediastinal doses (30 Gy or greater), minimal protective cardiac blocking and young age at irradiation. ^{149, 152} These observations support the use of combined modality, low-dose irradiation regimens in children and adolescents and suggest the need for cardiac screening of treated patients. Evidence level 2+

Whilst there is evidence that irradiation at levels over 30 to 35 Gy is a risk factor for cardiac disease in later life, there is insufficient evidence to comment on the lower dose range of 20 to 25 Gy. Irradiation induces atheromatous lesions of the proximal part of the coronary arteries. There is some evidence that high density lipoprotein blood levels may be altered after radiotherapy.^{148, 149, 151, 152, 153, 154, 155, 156, 160, 174} Evidence level 2+

Healthcare professionals should be aware that mediastinal irradiation over 30 Gy is a risk factor for cardiac disease in later life and monitoring is necessary.

Exposure to anthracyclines and obesity⁴⁶ are independent risk factors for congestive cardiac failure.

5.2 Assessment for cardiac problems

The literature has concentrated on the use of echocardiography in the assessment of cardiac dysfunction as this is non-invasive and widely available. The measurement of fractional shortening is least affected by mathematical error compared with other measures. The sensitivity of echocardiography is increased by introducing more invasive tests such as a dopamine stress test. Such tests are unlikely to be routine but may be reserved for patients in whom there may be difficulties discriminating normal from mildly abnormal fractional shortening measurements, and in particular, those taking part in competitive sports.^{163, 164, 171, 172} Evidence level 2+

Deterioration of cardiac function during treatment for childhood cancer correlates with increasing anthracycline dose, with evidence of cardiac dysfunction at relatively low doses. Evidence level 2+

The literature supports the use of echocardiography at diagnosis of the malignancy and at regular intervals during treatment in order to assess cardiac function.¹⁸⁸ Involvement of a paediatric cardiologist may be appropriate. Evidence level 2+

Although not based on evidence, in the opinion of the guideline development group a recommendation for echocardiograms at regular intervals (which may be dose determined) during treatment and every three years thereafter is practical and widely achievable. More frequent assessment should be instituted should clinical evidence of cardiac dysfunction develop.

Children with satisfactory left ventricular function on simple echocardiographic measures, who have received modest cumulative anthracycline doses (<250 mg/m2) may benefit from three-yearly echocardiogram surveillance.

Detailed cardiological assessment is appropriate for survivors of childhood cancer: who are pregnant or planning a pregnancy who wish to take part in competitive sports.

5.3 Treatment for cardiac problems

There is relatively little literature on the effective treatment of anthracycline-induced cardiac dysfunction.

The angiotensin converting enzyme inhibitors, captopril and enalapril, are currently used in the treatment of patients with reduced cardiac function secondary to anthracycline therapy. Initial benefit has been demonstrated, but it is not yet apparent whether early treatment benefit translates into improved long term outcome.^{189, 190} Research is currently underway to address these issues.¹⁹¹ Evidence level 2+,3

Survivors of childhood cancer with demonstrably impaired cardiac function may benefit symptomatically from treatment with angiotensin converting enzyme inhibitors, their left ventricular function may deteriorate with time despite continuing treatment. Cardiac function in some patients will deteriorate to a level requiring cardiac transplantation.¹⁹² Evidence level 2+

There is no evidence in the literature to recommend limiting employment and activity in these patients. The knowledge that exercise reduces systemic vascular resistance (and also cardiovascular risk) suggests that moderate physical activity should be encouraged.

Survivors of childhood cancer should be advised from a young age to: follow a healthy diet take regular exercise avoid taking up smoking or to aim towards smoking cessation.

* Liposomal daunorubicin has been withdrawn from the market

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