4. What is the risk for different cardiac RT doses for developing (a)symptomatic cardiac systolic dysfunction in childhood and young adult cancer survivors?
Author Year	Study Design Treatment era Years of follow-up	Participants	Treatment	Main outcomes	Addt’l remarks
Symptomatic cardiomyopathy and radiation dose
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
Schellong30 2010	Prospective cohort 1978–1995 15.1 yrs (3.1–29.4)	Hodgkin lymphoma: All pts. treated on German HD-78 to HD90 studies XRT field/dose reduction Uniform anth. dose Age at Dx:12.8 (2.5–17.9) Cardiac screening recs: Every 2–3 yrs up to 10 yrs Every 5 years thereafter In person +questionnaire	1132 eligible survivors Anthracyclines: 160mg/m2 everyone Mediastinal XRT: Median 25Gy (8–50) Mediast RT (MedRT) ≥36 Gy: 248 (21.9%) 30 Gy: 133 (11.7%) 25 Gy: 282 (24.9%) 20 Gy: 171 (15.1%) None: 298 (26.3%)	Cardiac grading per ACC/AHA 50/1132 (4.4%) w/ cardiac dz 14/1132 (1.2%) w/myocardial dz. 10/14 (71%) – MedRD-36 3/14 – MedRD20–30 25-yr CI of non-valvular cards dz ≥36 Gy: 4%, 30 Gy: 9%, 25 Gy: 4%, 20 Gy: 5%, None: 3%; p=0.2 Cox-regression: MedRD only predictor	Low prevalence/ incidence of myocardial disease likely due to low dose of anthracycline. Large study, long f/up, XRT is the only modified cardiotoxic exposure Unable to look at anth+XRT Non-valvular card dz includes CADz, valvular, conduction Homogeneous patient pop (age)
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%	CV outcomes Graded per: CTCAE v. 3.0 CHF (N=248) – HR 5.9 (3.4–9.6) Multivariate (CHF): No cardiac radiation (Ref) <5 Gy: HR 0.9 (0.6–1.4) 5–15 Gy: HR 1.3 (0.7–2.5) 15–35Gy: HR 2.2 (1.4–3.5) ≥35Gy: HR (4.5 (2.8–7.2) Dose-dependent increase in cumulative incidence of CHF	Self-reported Large sample size Long-term follow-up Cardiac XRT dosimetry calculations (Stovall et al.) Significance emerges at 15–35Gy XRT data not mutually exclusive of anthracycline exposure.
Blanco3 2012	Case-Control 1966–2008	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): Chest radiation None (Ref) Any: OR 4.29 (1.9–9.6), p<0.001	Largest pop of clinically validated DCM, CHF XRT prevalence difference, but no info on dosimetry.
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 No dosimetry for cardiac XRT Includes older treatment era
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: Any 21.2% None 78.7% Unknown 0.1%	CI and risk factors for A-CHF Univariate (CHF): RT on heart: RR 0.67 (0.2–2.3), NS Multivariate (CHF): No association with chest RT reported.	Not limited to long-term survivors No XRT dosimetry reported
Guldner32 2006	Retrospective cohort Cross-sectional eval 1968–1985 5.4 yrs	447 eligible based on anthracycline exposure No XRT alone pop. 245 (N=55%) participated in study Age at Dx: 6.2 (0–21 yrs)	Anthracyclines: Median: 300 mg/m2 Entire cohort XRT heart dose: Mean 8.1 (15.6)	140 examined and healthy 24 with cardiac failure 65 with other cardiac disorders Heart radiation dose: Healthy vs. heart failure: 0.6 Gy vs. 17.8 Gy, p<0.001 Dose-dependent increase in HF risk by radiation dose	No XRT heart dosimetry, dosing estimated
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%) 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) Avg. XRT dose to heart, p<0.001 0 No XRT (Ref) >0–5 Gy: 1.63 (0.82–3.26) >5–20 Gy: 6.48 (2.76–15.20) >20 Gy: 4.40 (1.11–17.48)	High proportion treated with chest radiation Very long term follow-up One of the earlier studies to demonstrate dose-resposne with XRT
Adams33 2004	Cross-sectional 1970–1991 14.3 (5.9–27.5)	Hodgkin Lymphoma 24% participation rate Age at diagnosis: Median 16.5 (6.3–25.0) Age at study visit: Median 31.9 (18–49)	Anthracycline: 4/48 (8.3%) Mediastinal XRT dose: Median 40 Gy (27–52)	Comprehensive echo evaluation and stress testing No discussion of CHF Very few had systolic dysfunction Most with indices of diastolic dysfunction	Very long-term follow-up One of few studies to evaluate XRT without anthracyclines Homogeneous population with not much variance in XRT dose Poor participation rate
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 Risk of CHF est. to increase by factor of 1.6 for every 10 Gy of lung XRT, 1.8 for every 10Gy of left abd. XRT (no effect for Right) Multivariate regression (inclanth) Lung XRT: None (Ref) 10–19.9 Gy: RR 1.5 (0.6–3.9), p-0.4 ≥20 Gy: 4.3 (0.8–24), p=0.1 L. Abd XRT: None or right (Ref) Left: RR 4.0 (1.4–11.6)	Homogeneous population due to diagnosis, the vast majority were exposed before 7 yo Results approach sig at high dose lung XRT
Van der Pal34 2005	Systematic review of risk of morbidity and mortality from cardiovascular disease for childhood cancer Lit Review: 1966–2002	Criteria for review: Original report English, Dutch, French, German Study pop.: >50 pts. Childhood CA: <=18 y. XRT involving heart region Outcome: Clinical cardiovascular event (CVE) or cardiovascular mortality	Many studies include arterial events (ie: MI) and CHF as CVE. For CVE: 9 studies selected based on validity and inclusion criteria. 8/9 studies, outcome well-defined 3/9 risk estimation well-defined and adequate	Relative Risk for CVE: Cardiac event, matched for anthracycline, time at risk, cohort Continuous tx. Variables (RR): Female/Male: 4.5, p<0.01 Anth, 100 mg/m2: 3.2, p<0.01 Lung RT, 10 Gy: 1.6, p=0.06 Left abd, 10 Gy: 1.8, p=0.02 Right abd. 10 Gy: 0.94, p=0.77 Categorical tx. Variables (RR): Female/Male: 3.7, p<0.01 Anth,>300 mg/m2: 5.0, p<0.02 Lung RT >20Gy: 3.1, p=0.21 Left abd. RT: 3.5, p=0.02	Older treatment eras For many, no clear delineation between RT-related systolic heart failure vs. CHF due to coronary artery disease, or MI alone. Dose-dependent Risk
Kremer21 2002	Review of Frequency and Risk Factors of anthracycline- induced clinical heart failure Medline: 1966–2000	71 articles reviewed Limitations in many: issing info Lack of RF analysis Non-rep. populations	Assess RR of possible Risk factors in 10 studies	Univariate (CHF): Risk with XRT reported in 4 out of 10 studies (3 out of 4 significant) Gilladoga (1976) N=50 XRT to heart: RR 5.2 (1.6–16.8) Dearth (1984) N=116 XRT to heat: RR13.5 (3.4–53.3) Bu’Lock (1996) N=226 XRT to heart: 11.1 (3.7–33.5) Krischer (1997) N=6493 XRT to heart: RR 0.7 (0.3–1.9)	Review is driven by anthracycline exposure Few with XRT dose quantification and none with careful heart dosimetry calculation
Asymptomatic cardiomyopathy and radiation dose (Abnormal EF, SF).
Brouwer22 2011	Cross-sectional 1976–1999 17.7 years	5-yr survivors 401 eligible 277 (69%) participated 8 (3%) on cardiac meds for CHF/renal	Anthracycline Median: 183 (50–600) Radiation 63%??	No breakdown by dose Multivariate LogisticRegression SF<29% Anthracycline ≥183: OR 2.2, 1.25–3.8, p<0.01 Mediast RT: 3.0, 1.4– 6.7,p<0.01 TBI: 1.9, 0.6–5.6	Good participation rates Comprehensive echo screen Long term follow-up Handful with clinical HF included in analysis
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% Cumm. XRT dose: ≤30 Gy 10.8% >30 Gy 23.2%	Asymptomatic cardiac dysf. Graded per CTCAE LVSF as primary outcome (1st echo) LVSF<30% XRT ≤30 vs. >30 Gy: 12.5% vs. 31% Multivariate regression (SF<30%): No Radiotherapy (Ref) Odds Ratio Thorax: 3.49 (1.6–7.6) Abdomen: 2.66 (1.0–7.05) Spine: 0.64 (0.23–1.74) TBI: 0.53 (0.10–2.87)
Abosoudah24 2011	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% No dose in modelField involving heart	Screening echo per COG LTFU GuidelinesNot limited to abn EF/FS Multivariate regression: No radiation (Ref) RT to heart: HR 1.7 (1.1–2.8)	Time to first abnormal echocardiogram Screening frequency driven by age, anthracycline dose, and XRT 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) Anth + XRT: 26.9% Chest XRT: 2.7%	Screening echo. LVSF, Wall stress Univariate regression (SF<28%): No Cardiac RT (Ref) RT: OR 0.9 (0.4–2.05)	Asymptomatic One time-point No cardiac dose quantification
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 10 studies w/RF analyses 6 studies which defined an abnormal SF with validity score>5	Risk Factor analysis: Steinherz (1991) Lipshutz (1991) Silber (1993) Sorensen (1995) Lipshultz (1995) Pihkala (1996) Sorensen (1997) Nysom (1998) Lanzarini (2000) Bossi (2001)	1 Study with chest radiation dose as predictor (limited to FS or EF abn) Risk Factor analysis: Steinherz (1991), N=201 >cumulative anth dose × f/up >mediastinal radiation No dose-effect calculations	Not all 10 studies had populations that would have received chest radiation (ie: ALL, AML)