7. What is the additional effect of radiotherapy on developing (a)symptomatic cardiac systolic dysfunction in childhood and young adult cancer survivors treated with anthracyclines?
First Author Year	Study Design Treatment era Years of follow- up	Participants	Treatment	Main outcomes	Addt’l remarks
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% Anth+XRT: 7.9% Median Anth: 250 mg/m2 (25–775) Cardiac irradiation: None (80.4%) Any (19.5%) Localization of XRT: Thorax (31.6%) Abdomen (24.4%) Spine (33.5%) TBI (10.5%) Cardiac XRT (EQD2): Thorax: 24 (9.5–88.5) Abd: 26.9 (3.7–57) Spine: 30.14 (8–50) TBI: 15.8 (14–21.6)	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 CI of CHF: Radiotherapy only: 0.7% at 30-yrs XRT + Anth: 7.9% at 30yrs Multivariate regression (Model 1) Radiotherapy (per 10 Gy) HR 1.4 (1.1–2.0) Multivariate regression (Model 2) Radiotherapy (Yes vs. No) HR 6.6 (0.6–73), p=0.13 Anth + Radiotherapy (Yes vs. No) HR 55.9 (6.6–470), p<0.001	Clinically validated outcomes Long follow-up, large cohort XRT dose conversion: Fractions of 2 Gy (EQD2) – includes both fractionation size and total dose Model 2 removes mutually exclusive cardiotoxic treatments. Radiotherapy alone not significant for CHF, but is predictive of other cardiac events
Aleman31 2007	Retrospective cohort 1965–1995 8.7 yrs (28 669 person-years for cohort)	5-year survivors of HL Age at treatment: <20 yo (21.3%) 20–35 yo (63.4%) >35 yo (15.3%) Age at f/up: <35 yo (16.6%) >55 yo (20.1%)	RT only 27.5% Chemo (CT) only 4.8% RT + CT, anth 29.5% RT + CT, no anth 38% Unknown 0.2% 17% recent smokers 10% HTN 5% diabetes 8.5% Dyslipidemia	Cumulative incidence of CHF 25y: No RT 0.4% Mediastinal RT only 6.8% Mediast RT + CT, no anth 4.9% Mediast RT + CT, anth 7.9% Multivariate regression (CHF): Model 2 Mediastinal RT only (Ref) Med. RT + CT, no anthracycline: RR 1.3 (0.79–2.24) Med. RT + CT, anthracycline: RR 2.81 (1.44–5.49)	Large pop of adult lymphoma survivors (most <35 yo at Dx) Very long follow-up Critical role of cardiovascular risk factors Suggest that RT alone no inc. risk for CHF? Ref group is RT Includes older treatment era
Pein19 2004 Br J Ca	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%) XRT dose to heart: Mean 6.7 Gy (0–91) Max 31.3 Gy (0–125)	Clear increase incidence w/time Multivariate regression: Cardiac failure, FS<25, EF<50, or ESWS>100 (not limited to CHF) <250 mg/m2 Dox <5Gy to the heart (Ref) ≥5 Gy: RR 4.9 (1.3–18) ≥250 mg/m2 Dox <5Gy + <250 anth (Ref) <5Gy: RR 5.1 (1.8–14.5) ≥5 Gy: RR 6.6 (2.1–20.6)	High proportion treated with chest radiation Very long term follow-up One of the earlier studies to demonstrate dose-response with XRT Potential interaction with anthracycline, with highest risk among those exposed to HD-anth and XRT