Table 2.
Prevalence of acute and early-onset cardiotoxicity in children with cancer treated with anthracyclines, mitoxantrone and/or radiotherapy involving the heart
| Study | Definition of cardiotoxicity | Timing of onseta | Prevalence (n/N) | Prevalence (%; 95% CI) |
|---|---|---|---|---|
| Echocardiography – systolic dysfunction | ||||
| Fractional shortening | ||||
| Chen 2009 [32] | < 28% | Acute/early | 2/168 | 1.2; 0.3–4.2 |
| Mavinkurve-Groothuis 2013 [49] | Early | 0/60 | 0.0; 0.0–6.0 | |
| Tan 2021 [67] | Acute/early | 15/458 | 3.3; 2.0–5.3 | |
| Agha 2016 [27] | Acute/early | 2/30 | 6.7; 1.8–21.3 | |
| Decrease > 10% of baseline | 12/30 | 40.0; 24.6–57.7 | ||
| De Matos Neto 2006 [36] | ≤ 29% or decrease ≥ 10% of baseline | Acute/early | 7/37 | 18.9; 9.5–34.2 |
| Kremer 2002 [13] | < 30% or decrease ≥ 15% of baseline | Early | 7/32 | 21.9; 11.0–38.8 |
| Krischke 2016 [48] | Once < 28% | Acute/early | 6/101 | 5.9; 2.8–12.4 |
| Once or more ≤ 30% | 20/101 | 19.8; 13.2–28.6 | ||
| Ejection fraction | ||||
| Fukumi 2002 [39] | < 50% | Acute/early | 0/29 | 0.0; 0.0–11.7 |
| Hagag 2019 [42] | Acute/early | 0/40 | 0.0; 0.0–8.8 | |
| Linares Ballesteros 2021 [64] | < 53% | Acute | 0/112 | 0.0; 0.0–3.3 |
| Early | 20/112 | 17.9; 11.9–26.0 | ||
| Moyo 2021 [65] | Decrease ≥ 10% to a final value of < 50% | Acute/early | 0/92 | 0.0; 0.0–4.0 |
| Samosir 2021 [66] | < 50% or decrease > 10% of baseline | Acute/early | 5/49 | 10.2; 4.4–21.8 |
| Brown 2013 [31] | Decrease > 10% of baseline | Acute/early | 10/71 | 14.1; 7.8–24.0 |
| Berrak 2001 [30] | Decrease > 15% of baseline | Early | 1/97 | 1.0; 0.2–5.6 |
| Gupta 2018 [41] | Decrease ≥ 20% of baseline | Early | 3/40 | 7.5; 2.6–19.9 |
| Fractional shortening or ejection fraction | ||||
| Erkus 2007 [38] | FS < 29% or EF < 55% | Early | 0/29 | 0.0; 0.0–11.7 |
| Moussa 2017 [51] | FS ≤ 28% or EF ≤ 58% | Acute/early | 31/149 | 20.8; 15.1–28.0 |
| Global longitudinal strain | ||||
| Cheung 2020 | Decrease ≥ 20% | Early | 22/39 | 56.4; 41.0–70.7 |
| Echocardiography – diastolic dysfunction | ||||
| Tei index | ||||
| Ishii 2000 [45] | > 0.35 | Acute/early | ANT < 200 mg/m2: 9/30 | 30.0; 16.7–47.9 |
| ANT ≥ 200/ < 400 mg/m2: 25/30 | 83.3; 66.4–92.7 | |||
| ANT ≥ 400 mg/m2: 12/12 | 100; 75.8–100 | |||
| E/A ratio | ||||
| Oztarhan 2011 [52] | < 1 | Acute/early | 91/251 | 36.3; 30.6–42.4 |
| Combination of echocardiographic and/or clinical parameters | ||||
| National Cancer Institute – Common Terminology Criteria for Adverse Events | ||||
| Creutzig 2007 [35] | Version nm | Acute/early | LVSD/FS, grade 1: 11/885 | 1.2; 0.7–2.2 |
| LVSD/FS, grade 2: 9/885 | 1.0; 0.5–1.9 | |||
| Asselin 2016 [29] | Version 2.0 | Acute/early | LVSD/FS, grade 3 or 4: 3/624 | 0.5; 0.2–1.4 |
| Schramm 2019 [55] | Acute/early | LVSD/EF, grade 1: 3/229 | 1.3; 0.4–3.8 | |
| LVSD/EF, grade 3: 2/229 | 0.9; 0.2–3.1 | |||
| LVSD/FS, grade 1: 3/175 | 1.7; 0.6–4.9 | |||
| Getz 2019 [40] | Version 3.0 | Acute/early | LVSD/FS or EF, grade 2 or higher: 118/795 | 14.8; 12.5–17.5 |
| Brown 2013 [31] | Version 3.0/4.0 | Acute/early | LVSD/EF, grade 1: 25/71 | 35.2; 25.1–46.8 |
| LVSD/EF, grade 2: 10/71b | 14.1; 7.8–24.0 | |||
| LVSD/EF, grade 3: 5/71 | 7.0; 3.0–15.4 | |||
| Katzenstein 2022 [63] | Acute/early | LVSD, grade 3 or higher: 1/102 | 1.0; 0.2–5.3 | |
| RVD, grade 3 or higher: 1/102 | 1.0; 0.2–5.3 | |||
| Cardiopulmonary arrest, grade 4: 2/102 | 2.0; 0.5–6.9 | |||
| Burke 2021 [61] | Version 4.0 | Acute/early | LVSD/FS or EF, grade 2: 1/46 | 2.2; 0.4–11.3 |
| Tringale 2022 [69] | Version 5.0 | Acute/early | Grade 2 ‘left-ventricular strain’: 1/50 | 2.0; 0.4–10.5 |
| Yu 2021 [70] | Acute/early | LVSD/EF: 0/171c | 0.0; 0.0–2.2 | |
| Combination of echocardiographic parameters | ||||
| Choi 2010 [34] | FS < 28% or increased ventricular diastolic or systolic diameter for age | Acute/early | 16/42 | 38.1; 25.0–53.2 |
| Combination of echocardiographic and clinical parameters | ||||
| Cheung 2020 | Clinical heart failure or reduced EF | Acute | 0/39 | 0.0; 0.0–9.0 |
| Early | 0/39 | 0.0; 0.0–9.0 | ||
| Hu 2018 (2) [44] | EF < 53% and heart failure symptoms | Early | 2/131 | 1.5; 0.4–5.4 |
| Kang 2012 [46] | EF < 45% or evidence of clinical congestive heart failure | Acute/early | 9/123 | 7.3; 3.9–13.3 |
| Moke 2018 [50] | FS < 25% or decrease of > 10% of baseline; EF < 50% or decrease of > 10% of baseline; ventricular dilation; cardiomyopathy; E/A reversal; valve abnormality or arrhythmia leading to cardiology referral or cardiac medication initiation | Early | 8/368 | 2.2; 1.1–4.2 |
| Stöhr 2006 [57] | FS < 29% without clinical symptoms (subclinical cardiomyopathy) | Acute/early | 2/172 | 1.2; 0.3–4.1 |
| FS < 29% with clinical symptoms (clinical cardiomyopathy) | 1/172 | 0.6; 0.1–3.2 | ||
| Tantawy 2011 [58] | EF < 50% | Acute/early | 12/39 | 30.8; 18.6–46.4 |
| Clinical heart failure | 0/39 | 0.0; 0.0–9.0 | ||
| Temming 2011 [59] | FS < 28% without clinical symptoms (subclinical cardiomyopathy) | Acute/early | 6/95 | 6.3; 2.9–13.1 |
| FS < 28% with clinical symptoms (clinical cardiomyopathy) | 7/95 | 7.4; 3.6–14.4 | ||
| Clinical symptoms | ||||
| Creutzig 2007 [35] | Clinical signs and symptoms of cardiomyopathy not attributable to other known causes such as sepsis or renal failure | Acute/early | 14/885 | 1.6; 0.9–2.6 |
| Hu 2018 (1) [43] | Heart failure | Early | 0/36 | 0.0; 0.0–9.6 |
| Shaikh 2013 [59] | Cardiac dysfunction | Acute/early | 28/110 | 25.5; 18.2–34.3 |
| Tang 2020 | Chemotherapy-related severe myocardial damage or impaired cardiac function | Acute/early | 0/102 | 0.0; 0.0–3.6 |
| Van Dalen 2006 [23] | Congestive heart failure defined as the presence of following clinical signs: dyspnea, pulmonary oedema, peripheral oedema and/or exercise intolerance, which were treated with anticongestive therapy | Acute/early | 16/830 | 1.9; 1.2–3.1 |
| Biomarker levels | ||||
| Gupta 2018 [41] | proBNP ≥ 100 pg/mL | Early | 15/40 | 37.5; 24.2–53.0 |
| Linares Ballesteros 2021 [64] | BNP > 100 pg/mL | Early | 26/112 | 23.2; 16.4–31.8 |
| TnI > 0.05 ng/L | 0/112 | 0.0; 0.0–3.3 | ||
| TnT > 0.04 ng/mL | 0/112 | 0.0; 0.0–3.3 | ||
| Mavinkurve-Groothuis 2013 [49] | NT-proBNP > 97.5th percentile | Early | 8/41 | 19.5; 10.2–34.0 |
| cTnT > 0.01 ng/mL | 1/41 | 2.4; 0.4–12.6 | ||
| Erkus 2007 [38] | cTnI > 0.04 ng/mL | Early | 2/29 | 6.9; 1.9–22.0 |
| Asselin 2016 [29] | cTnT > 0.01 ng/mL | Acute/early | 10/114 | 8.8; 4.8–15.4 |
| Kremer 2002 [13] | cTnT > 0.040 ng/mL | Acute | 3/38 | 7.9; 2.7–20.8 |
| Early | 1/31 | 3.2; 0.6–16.2 | ||
Abbreviations: ANT Cumulative anthracycline dose, BNP Brain natriuretic peptide, CI Confidence interval, cTnI Cardiac troponin I, cTnT Cardiac troponin T, EF Ejection fraction, FS Fractional shortening, LVSD Left ventricular systolic dysfunction, NCI CTCAE National Cancer Institute – Common Terminology Criteria for Adverse Events, NT-proBNP N-terminal prohormone of brain natriuretic peptide, proBNP Prohormone of brain natriuretic peptide, RVD Right ventricular dysfunction, TnI Troponin I, TnT Troponin T
aacute (within one week after a treatment); early (within one year after start of treatment); acute/early (acute and early not separable)
b an additional 10/71 (14.1%; 95% CI 7.8–24.0) had 10–19% decrease from baseline ejection fraction (version 4.0, grade 2)
c31/171 (18.1%; 95% CI 13.1–24.6) showed echo abnormalities including pericardial effusion (N = 14), left ventricular hypertrophy (N = 11), widened pulmonary artery (N = 5) and valve disease (N = 5), not graded according to NCI CTCAE