5. What is the additional effect of age at treatment on developing (a)symptomatic cardiac systolic dysfunction
First Author Year	Study Design Treatment era Years of follow-up	Participants	Treatment	Main outcomes	Addt’l remarks
Symptomatic cardiomyopathy and age
van der Pal1 2012	Retrospective cohort 1966–1996 22.2 yrs (5.0–44.5)	5-yr survivors (N=1362) Age at Dx: 5.9 (0–18)	Anthracyclines: 33.6% Cardiac XRT: 19.5% Anth+XRT: 7.9% Median Anth: 250 (25–775)	Symptomatic cardiac events (CE) Grading: CTCAE v 3.0 50 CEs in 42 CS (CHF in 27/50) Median time to event: 18.6 yrs Multivariate (CHF): Age at Dx (per year): HR 0.98, NS	Clinically validated outcomes
Mulrooney2 2009	Retrospective cohort 1970–1986 27.0 yrs (8–51)	5-yr Survivors (N=14, 358) Age at Dx: 0–4 yrs: 40.1% 5–9 yrs: 22.3% 10–14 yrs: 20.3% 15–20 yrs: 17.3% Siblings (N=3899)	Anthracyclines: 33.1% No Cardiac XRT: 29% <5 Gy: 34% 5–15 Gy: 5.8% 15–35Gy: 9.7% >=35Gy: 6.9%	Self-reported CV outcomes Graded per CTCAE v. 3.0 CHF (N=248) – HR 5.9 (3.4–9.6) Multivariate (CHF): Age at Dx: 0–4 yrs – HR 3.9 (2.1–7.3) 5–9 yrs – HR 2.3 (1.3–4.0) 10–14 yrs – HR 1.2 (0.8–1.9) 15–20 yrs – Ref	Self-reported Large sample size Long-term follow-up
Blanco3 2012	Case-Control 1966–2008 Cases: 9.2 (0.1–35.1) Controls: 12.3 (0.4–40)	Case (CHF) – N=170 Control (none) – N=317 Matching criteria: Diagnosis Year of Dx (+/−5 yrs) Race/ethnicity Follow-up (controls)	Cases vs. controls: Anthracyclines 291 vs. 168, p<0.01 Chest XRT 25% vs. 14%, p<0.01	Clinically validated DCM, CHF Genetic susceptibility Multivariate (CHF): Age at dx (per year): 0.99, NS	Largest pop of clinically validated DCM, CHF Ca-Co matched on diagnosis, by default would have also matched on Age at diagnosis (exposure)
Temming4 2011	Retrospective cohort 1987–2004 7.3 yrs (0–21.7)	124/158 available for Cardiotox analysis 86 data for late cardiotox Age at Dx: 2.9 (0.1–12.9)	AML 10 and 12 trials Anthracyclines: Dauno and Mitox (1:5 conversion) 550–610 mg/m2	Subclinical cardiotox (SF<28%) Clinical CHF per AHA Multivariate (CHF): Age <4 yrs: 0.76 (0.20–2.94) Age >=4 (Ref)	Not a very wide distribution of age due to Dx.
Creutzig5 2007	Retrospective cohort 1993–2003 BFM98: 3.6ys (0.8–7.0) BFM93: 7.5ys (1.1–11) Median F/up late cartox: 5.3 (0.8–11.5)	Eligible: N=1207 Late Cartox evaluated: N=547 (45%) 76% of echo evaluations done within first 5yrs Age at diagnosis not provided, all <18 y.o.	AML BFM 93 and 98 Dauno : Ida – 1:5 Dauno : Mitox – 1:5 Anth dose: B 93: 300–400 mg/m2 B 98: 420–450 mg/m2	CI of late cardiotoxicity: 5% +/1 % (includes subset with early cardiotoxicity) No difference by randomization: Dauno vs. Ida Cox Regression: Age, early cartox, FAB Early cartox only predictor of late	Early and late cardiotoxicity. Study summary only presents data on late cardiotoxicity. Sig. #’s lost to follow-up Homogeneous pop: Age, Anthracycline dose ??Role of HCT
van Dalen18 2006	Retrospective cohort 1976–2001 8.5 yrs (0.01–28.4) F/up on prev 2001 JCO study	830 Children treated with anthracyclines Age at Anth exposure: <2 – 9.2% 2–6 – 30.9% 7–11 – 27% 12–16 – 30.2% >16 – 2.7%	Anthracyclines: Mean –288 (15–900) Chest XRT: 21.2% Mitoxantrone: Any 4.1%	CI and risk factors for A-CHF Univariate (CHF): Age <=2 yrs = RR 0.28 (0.04–2.1) Multivariate (CHF): No association with age	Not limited to long-term survivors
Pein19 2004	Retrospective cohort 1968–1982 18 yrs	Original cohort: 447 218 (48.8%) not evaluated 229 (51.2%) echo’s 15+year survivors Age at treatment: 6.2 yrs (0–21)	Anthracycline: 344 mg/m2 (40–600) Radiotherapy: 245 (55%)	Clear increase CHD incidence over time Univariate regression: Cardiac failure, FS<25, EF<50, or ESWS>100 (not limited to clinical CHF) >=8 yrs (Ref) 0–7 years: RR 2.63 (0.87–7.96) P-Value 0.08??	High proportion treated with chest radiation Very long term follow-up No mention if age was significant in multivariate regression model
Green20 2001	Retrospective cohort Case-Control Through 1998	NWTS 1–4 Cohort 1: 1–4 received dox N=2,843 Cohort 2: 1–3, dox as part of salvage only (N=228) Age at Dx: 80% <8 y.o.	Anthracyclines Chest XRT – mostly due to lung XRT	CI and risk factors for CHF Age not included in multivariate model	Homogeneous population due to diagnosis, the vast majority were exposed before 7 yo
Kremer21 2002	Review of Frequency and Risk Factors of anthracycline-induced clinical heart failure Medline: 1966–2000	71 articles reviewed Limitations in many: Missing info Lack of RF analysis Non-rep. populations	Assess RR of possible Risk factors in 10 studies	1 out of 10 studies: Age <4 years as predictor of CHF Godoy (1997), N=69 RR = 11.7 (1.4–96.4)	Unclear If lack of association with age in the other 9 studies b/c age not evaluated or non-significant.
Asymptomatic cardiomyopathy and age (Abnormal EF, SF)
van der Pal23 2010	Prospective cohort-Survivorship clinic 1966–1997 15.4 yrs (5.1–4.3)	5-yr survivors 735 anthracycline-treated 601 Eligible for study 525 Had echocardiogram Age at Dx: 8.9 (0.1–17.8)	Anthracycline: Med – 250 (33–720) Chest XRT: 36.4%	Asymptomatic cardiac dysf. Graded per CTCAE LVSF as primary outcome (1st echo) Multivariate regression (SF<30%): Age at dx 0–5yr – OR 2.94 (1.08–8.02) >5–10 – OR 1.64 (0.67–4.01) >10–15 – (0.64–3.28) >15 – Ref
Abosoudah24 2010	Prospective cohort-Survivorship clinic 1995–2003 3.0 yrs (1–10)	4-year survivors 896 anthracycline-treated 603 eligible for study 469 >=1 screening echo Age at Dx: 7.7 (SD 4.6)	Anthracycline: Mean – 205 (114.7) Chest XRT: 34%	Screening echo per COG LTFU Guidelines Not limited to abn EF/FS Multivariate regression: Age at tx: 1–4 yrs – 1.89 (1.1–3.3); Ref >=5	Time to first abnormal echocardiogram Unclear for transients Screening frequency driven by age, so unclear implication
Hudson25 2007	Cross-sectional 9.0 (3.0–18.0)	223 anthracycline-treated Vs. 55 – not at risk Age at Dx: 5.5 (0–23.6)	Anthracycline (AR) Med: 202 (25–510) Chest XRT: 29% Anth + XRT: 26.9%	Screening echo. LVSF, Wall stress Multivariate regression (SF<28%): Age at dx >=5 yrs – OR 2.41 (0.9–6.4), p0.08 <5 Ref	Asymptomatic One time-point
Paulides26 2006	Prospective cohort 1992–2004 3 yrs (+/−1 yr)	LESS -sarcoma 1066 non-relapse cohort 564 excluded (addt’l anth) Age at tx: 13 +/5 yrs	Anthracycline: Mean – 290+/−91 Chest XRT: 6.8%	Subclinical FS<29%×2 Clinical CHF – per AHA 4/265 Clinical CHF 16/265 subclinical DCM No regression analyses	Clinical and subclinical DCM Homogeneous cohort, similar age, so not as clear Short follow-up
Sorensen28 2003	Prospective cohort 1970–1990 6.2–6.7 years from Dx	ALL survivors – N=101 Age dx: 4.8 +/−2.7 Wilm;s – N=83 Age dx: 4.1 +/−2.3 2 Echo’s mean 4 years apart.	Anthracycline: ALL – 180 +/−73 WT – 301 +/−78	Comprehensive echo. Intermediate indices + FS Multivariate linear regression FS at second timepoint (FS2) Age (yrs): −0.09 (−0.35, +0.16) Difference in FS over time Age (yrs): +0.18 (−0.09, +0.45)	Homogeneous populations: ALL and Wilm’s Essentially comparing high dose vs. low-dose anthracycline with no heterogeneity in age
Kremer29 2002	Review of Frequency and Risk Factors of anthracycline-induced subclinical cardiotoxicity Medline: 1966–2001 >50 children/study	58 articles reviewed Limitations in many: Missing info Non-rep. populations Non-original research Validity evaluated in 25 studies RF analyses in 10	Steinherz (1991) Lipshutz (1991) Silber (1993) Sorensen (1995) Lipshultz (1995) Pihkala (1996) Sorensen (1997) Nysom (1998) Lanzarini (2000) Bossi (2001)	Studies with age as predictor (limited to FS or EF abn) Silber 1993 -<age at tx Lipshultz 1995 -<age at dx Sorensen 1997 ->age at tx	Several studies with associations with age and other indices (ie: ESWS, SVI, wall thickness)