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Anthracycline Cardiotoxicity

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Background

As more information is gathered, the more concerning this late effect becomes. The problem is that we do not have the tools to accurately measure acute myocardial toxicity that predicts chronic toxicity. Although abnormal fractional shortening during therapy predicts chronic toxicity, young patients with normal fractional shortening while on therapy remain at risk for subsequent cardiac problems. As the patient grows, previously masked myocardial damage may become evident as the heart is unable to cope with an increasing blood volume. This is particularly evident during pregnancy and adolescence.

Current research in this area is looking at the effects individual genetic variations may have on anthracycline toxicity. This is both variations in the AUC of the anthracycline (pharmacokinetic genetic variations) and in the interplay of anthracycline induced damage with other genetic cardiac risk factors in the family history.

Pathogenesis

Anthracyclines generate free radicals (H202 and hydroxyl radicals) mainly by an Fe-dependent mechanism. Free radicals induce myocyte damage by causing lipid peroxidation and interfering with mitochondrial electron transport. In addition, anthracyclines deplete intracellular glutathione thereby exacerbating oxidative stress. Oxidative damage produces loss of myofibrils, and swelling of the sarcoplasmic reticulum and mitochondria.

Risk factors

  • Total cumulative dose of anthracycline - doses >400mg/m2 produce late-onset cardiac dysfunction in the majority of children. Doses >250mg/m2 cause diminished cardiac function in 2/3 of children. There is probably no safe dose of anthracycline.
  • Method of administration - it is possible that longer infusion times (6 - 48 hours) reduce myocardial damage but this remains unproven.
  • Type of anthracycline - epirubicin, idarubicin and mitozantrone are reported to be less cardiotoxic. Although idarubicin and mitozantrone are more cardiotoxic than daunorubicin and doxorubicin on a mg per mg basis, the dose used is much less so the overall effect is diminished. Meta-analysis has not been able to comfirm this as the majority of studies have been underpowered. There is good evidence that liposomal doxorubicin is less cardiotoxic.
  • Concurrent therapy - mediastinal radiotherapy and concurrent use of other chemotherapy agents eg. amsacrine, cyclophosphamide
  • Pre-exisiting cardiac conditions
  • Younger age
  • Down syndrome
  • Females

Note: myocardial dysfunction is more likely to be clinically manifested if there is additional cardiovascular stressor.

Clinical presentation

Most often, myocardial damage is detected when it is silent ie. on echocardiography, but it may present clinically:

  • acute onset of LVF during therapy possibly with evidence of pan-carditis
  • gradual onset of LVF off therapy
  • arrythmias

Evaluation

The most commonly used technique is echocardiographic measurement of fractional shortening:

Fractional shortening (%) = end systolic diameter of LV x 100 end diastolic diameter of LV.

This needs to be performed when the patient is NOT having hyperhydration.

An abnormal result is:

  • FS < 29%, or
  • Decline in FS > 10% from baseline value
  • Other echocardiogram indices of LV function - particularly global longitudinal strain - will detect LV dysfunction earlier, but their specificity in terms of predicting major immediate or long term problems is unknown.  

Other techniques:

  • Exercise echocardiograph - useful if patient is considering very active pursuits
  • Endomyocardial biopsy - confirms diagnosis if there is doubt but is not in itself prognostic so is rarely required
  • MUGA radionuclide scan (gated heart scan)

Prevention

Limiting the total dose is essential, it is important to record the cumulative dose per m2 each time an anthracycline is given (including all anthracyclines as mg doxorubicin equivalents). This is especially important in relapsed patients being re-treated. Most but not all protocols advise infusion over at least 6 hours. Other options should be discussed with the treating paediatric oncologist and include:

  • Liposomal encapsulated daunorubicin (Daunoxome) and doxorubicin (Doxil). These have been shown to have some cardioprotective effects in adults (primarily with breast cancer patients) but trials as to the comparative cardiotoxicity are still ongoing.
  • Cardioprotectants - dexrazoxane acts by chelating Fe. This agent is available but expensive. Small randomised controlled studies in children have shown improved cardiac parameters over the medium term for those receiving dexrazoxane and no apparent influence on efficacy of anticancer therapy.

Treatment

During chemotherapy

Echocardiographic and ECG assessment is carried out at regular intervals as specified in the protocol. If cardiotoxicity is suspected by measuring fractional shortening discuss with the treating paediatric oncologist. The usual approach is to withhold anthracyclines and repeat FS after 7 days.

  • If FS recovers - give anthracycline but increase frequency of echocardiograph monitoring to prior to each cycle if this is not already occurring. Consider dexrazoxane.
  • If FS remains abnormal - withhold further anthracylines. This decision needs to be made by the treating paediatric oncologist in the context of the patient's clinical situation and underlying cancer. It may be possible to give further anthracyclines with dexrazoxane but the family need to be advised of the risks of this situation.

After chemotherapy

Surveillance dependent on risk group - see below.

FS and/or ECG abnormal - refer to Paediatric Cardiologist.

Annual FS measurement may be recommended by cardiologist as part of cardiology followup.

ACE-inhibitors may be helpful for persistent significant decline in FS, but long-term effect on wall thickness concerning.

Some patients have undergone heart transplantation.

Harmonised recommendations for cardiomyopathy surveillance for survivors of childhood cancer

Who needs cardiomyopathy surveillance?
Strong recommendation:
- Survivors treated with high dose (≥250mg/m2) anthracyclines
- Survivors treated with high dose (≥35gy) chest radiation
- Survivors treated with moderate to high dose anthracyclines (≥100mg/m2) and moderate to high dose chest radiation (≥15gy) 
Moderate recommendation:
- Survivors treated with high dose (≥100 to <250mg/m2) anthracyclines
Weak recommendation:
- Survivors treated with low dose (≥100mg/m2) anthracyclines
- Survivors treated with moderate dose (>15 to 35gy) chest radiation
No recommendation:
<15gy radiation
What surveillance modality should be used?
Strong recommendation:
- Echocardiography as the primary modality to assess LV systolic function
Weak recommendation:
- Radionuclide angiography or cardiac MRI, in those survivors where ECHO is not technically feasible or optimal.
At what frequency should surveillance be performed for high risk survivors?
Strong recommendation:
- To begin no later than 2 years after completion of cardiotoxic therapy, repeated at 5 years after diagnosis and every 5 years thereafter
Moderate recommendation:
- More frequent surveillance in high risk survivors
Weak recommendation:
- Lifelong surveillance may be reasonable for high risk survivors
At what frequency should surveillance be performed for moderate or low risk survivors?
Strong recommendation:
To begin no later than 2 years after completion of cardiotoxic therapy, repeated at 5 years after diagnosis and every 5 years thereafter
Weak recommendation:
More frequent surveillance in moderate and low risk survivors
- Lifelong surveillance may be reasonable for moderate and low risk survivors
At what frequency should surveillance be performed for survivors who are pregnant or planning to become pregnant?
Strong recommendation:
Before pregnancy or in the first trimester for all female survivors treated with anthracyclines or chest radiation
No recommendation:
For the frequency of surveillance of pregnant survivors who have normal LV systolic function immediately before or during first trimester

References

  1. CALLCG group. Beneficial and harmful effects of anthracyclines in the treatment of childhood acute lymphoblastic leukaemia:a systematic review and meta-analysis. BJH 2009; 145(3):376-388.
  2. van Dalen EC et al. Different anthracycline derivates for reducing cardiotoxicity in cancer patients. Cochrane Database of Systematic Reviews. 2006a CD005006.
  3. Recommendations for cardiomyopathy surveillance for survivors of childhood cancer: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. The Lancet Vol 16 March 2015

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Document Control

  • Date last published: 06 July 2016
  • Document type: Clinical Guideline
  • Services responsible: National Child Cancer Network
  • Author(s): Jane Skeen, Tom Gentles
  • Owner: Jane Skeen
  • Review frequency: 2 years