Side effects of systemic cancer therapy - cardiomyopathy

Patterns

	Type I (anthracycline)	Type II (trastuzumab)
Mechanism	Myocyte death	Reversible HER2 blockade
Dose-related	Yes - cumulative	No
Reversibility	Largely irreversible	Largely reversible on cessation
Biopsy	Vacuolisation, myofibrillar loss	Little structural change
Re-challenge	No	Yes, once EF recovers

Emerging: checkpoint inhibitor myocarditis - rare (~1%) but fatality up to 50%; a fulminant inflammatory rather than degenerative process

Anthracycline - clinically overt heart failure ~5% at 400 mg/m2 doxorubicin, ~16% at 500, ~26-48% at 550
- Subclinical LV dysfunction far more common (~9-20%)
Trastuzumab - asymptomatic LVEF decline ~13%, symptomatic heart failure ~1.9%
- Risk multiplies with prior/concurrent anthracycline
Risk factors: prior anthracycline, age >50 (and <18), BMI >25, hypertension, diabetes, baseline LVEF <55%, pre-existing cardiac disease, mediastinal radiotherapy, female sex

Anthracyclines (doxorubicin, epirubicin, daunorubicin, idarubicin)

DNA intercalation + topoisomerase-IIbeta inhibition in cardiomyocytes
- -> mitochondrial dysfunction, DNA double-strand breaks
Iron-dependent reactive oxygen species generation; cardiomyocytes have low antioxidant reserve
-> myofibrillar disarray, vacuolisation, apoptosis -> irreversible myocyte loss
*Cumulative dose is the dominant determinant* - record lifetime anthracycline exposure in every survivor

Cardiomyocytes express HER2 (ErbB2); neuregulin-1/ErbB signalling is a survival and repair pathway
Blockade -> impaired stress response and repair, not cell death
-> reversible contractile dysfunction, worse if myocytes already damaged by anthracycline

VEGF/TKI (bevacizumab, sunitinib, sorafenib, lenvatinib) - hypertension-mediated + direct; usually reversible
5-FU/capecitabine - coronary vasospasm -> angina, infarction, arrhythmia
Checkpoint inhibitors - T-cell mediated myocarditis
CAR-T - CRS-associated cardiomyopathy
Proteasome inhibitors (carfilzomib) - heart failure, hypertension
BCR-ABL TKIs (ponatinib, nilotinib) - vascular occlusive events
Mediastinal/left breast radiotherapy - accelerated CAD, valvular disease, constrictive pericarditis, restrictive cardiomyopathy

Category	Criteria
Symptomatic	New heart failure symptoms, graded by severity
Moderate asymptomatic	LVEF fall >=10 points to 40-49%, OR LVEF fall <10 points to 40-49% with a new GLS fall >15% relative or a biomarker rise
Severe asymptomatic	LVEF <40%
Mild asymptomatic	LVEF >=50% with relative GLS fall >15% and/or new troponin/NP rise

*Global longitudinal strain falls before LVEF does* - the earliest reliable sign

Cardiovascular risk stratification before cardiotoxic therapy (HFA-ICOS proforma)
Baseline echo with LVEF and GLS, ECG, troponin, natriuretic peptide
Optimise BP, lipids, diabetes, smoking

Trastuzumab: echo or gated heart pool scan every 3 months during treatment, and at 6 and 12 months after
Anthracycline: echo before, after cumulative doses, at completion, and at 12 months; lifelong periodic review in high-risk survivors
Stop or hold if LVEF falls >=15 points below baseline (or below 45-50%) or the patient becomes symptomatic
Use the same modality and the same lab each time - inter-technique variability exceeds the effect size
CMR if echo is equivocal or myocarditis suspected

A. Prevention

Minimise cumulative anthracycline dose; use liposomal doxorubicin or continuous infusion in high-risk patients
Dexrazoxane - iron chelator/topoisomerase-IIbeta modulator; the only agent with robust protective evidence
- Consider at high cumulative anthracycline dose or high baseline risk
Cardiac-sparing radiotherapy - deep inspiration breath-hold for left breast
Treat hypertension, diabetes, dyslipidaemia aggressively before and during therapy
Exercise programs; alcohol reduction
Statins and ACE inhibitors/beta blockers as primary prevention: trial evidence is mixed - reserve for high baseline risk rather than everyone

B. Established CTRCD

Standard guideline-directed heart failure therapy - ACEi/ARNI, beta blocker (carvedilol widely used), MRA, SGLT2 inhibitor
- Start promptly - the shorter the interval from LVEF drop to treatment, the better the recovery
Cardiology/cardio-oncology referral

C. Continue or stop the cancer drug?

*This is a joint decision, not a unilateral cardiology one* - weigh the cancer's curability against the cardiac risk
Trastuzumab
- Hold if LVEF <45%, or falls >=10 points to <50%, or symptomatic
- Start heart failure therapy, repeat echo in 3-4 weeks
- Re-challenge once LVEF recovers to >=50% - most recover, and most tolerate resumption
Anthracycline - generally stop permanently; consider switching to a non-anthracycline regimen
Checkpoint inhibitor myocarditis - stop permanently, admit to a monitored bed, high-dose methylprednisolone 1 g daily
5-FU/capecitabine vasospasm - stop, nitrates/calcium channel blocker; re-challenge is hazardous

D. Survivorship

Lifelong cardiovascular risk factor management in anthracycline survivors, especially those treated in childhood
Document lifetime cumulative anthracycline dose and radiation fields in the discharge summary
Periodic echo in high-risk survivors; low threshold for imaging in pregnancy (peripartum decompensation is well described)

Anthracyclines (doxorubicin, epirubicin, daunorubicin, idarubicin, mitoxantrone)
Trastuzumab, pertuzumab, T-DM1, trastuzumab deruxtecan
VEGF inhibitors and multi-target TKIs; proteasome inhibitors (carfilzomib)
5-FU and capecitabine (vasospasm)
Checkpoint inhibitors (myocarditis, often with myositis and myasthenia - the "triple M")
CAR-T and bispecific T-cell engagers
Mediastinal radiotherapy - CAD, valve disease, constrictive pericarditis, conduction disease
Childhood cancer survivorship - the highest-risk population

Trastuzumab cardiotoxicity: mostly reversible - LVEF recovers in ~70-80% within 3-6 months of cessation + heart failure therapy
Anthracycline cardiotoxicity
- Acute (during infusion) - arrhythmia, pericarditis-myocarditis; rare, usually transient
- Early chronic - within the first year; the commonest and most treatable
- Late - years to decades later, especially in childhood cancer survivors; often presents in adolescence or with pregnancy
- Prognosis historically poor once symptomatic, but much better with early detection and modern heart failure therapy
Radiation heart disease has a latency of 10-20 years - constrictive pericarditis, valvular stenosis, ostial coronary disease
Checkpoint inhibitor myocarditis: fulminant, mortality up to 50% - the outlier in every respect
Cardiovascular disease is now a leading cause of non-cancer death in long-term survivors of breast cancer, lymphoma and childhood cancer

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