Risk Factors for Heart Failure Among Pan-European Childhood Cancer Survivors: A PanCareSurFup and ProCardio Cohort and Nested Case-Control Study

Abstract

Purpose: Heart failure (HF) is a potentially life-threatening complication of treatment for childhood cancer. We evaluated the risk and risk factors for HF in a large European study of long-term survivors. Little is known of the effects of low doses of treatment, which is needed to improve current treatment protocols and surveillance guidelines.

Methods: This study includes the PanCareSurFup and ProCardio cohort of ≥ 5-year childhood cancer survivors diagnosed between 1940 and 2009 in seven European countries (N = 42,361). We calculated the cumulative incidence of HF and conducted a nested case-control study to evaluate detailed treatment-related risk factors.

Results: The cumulative incidence of HF was 2% (95% CI, 1.7 to 2.2) by age 50 years. The case-control study (n = 1,000) showed that survivors who received a mean heart radiation therapy (RT) dose of 5 to < 15 Gy have an increased risk of HF (odds ratio, 5.5; 95% CI, 2.5 to 12.3), when compared with no heart RT. The risk associated with doses 5 to < 15 Gy increased with exposure of a larger heart volume. In addition, the HF risk increased in a linear fashion with higher mean heart RT doses. Regarding total cumulative anthracycline dose, survivors who received ≥ 100 mg/m² had a substantially increased risk of HF and survivors treated with a lower dose showed no significantly increased risk of HF. The dose-response relationship appeared quadratic with higher anthracycline doses.

Conclusion: Survivors who received a mean heart RT dose of ≥ 5 Gy have an increased risk of HF. The risk associated with RT increases with larger volumes exposed. Survivors treated with < 100 mg/m² total cumulative anthracycline dose have no significantly increased risk of HF. These new findings might have consequences for new treatment protocols for children with cancer and for cardiomyopathy surveillance guidelines.

FIG 1.

Cumulative incidence of heart failure for all survivors (including all types of treatment) with attained age as the time scale. Shaded: 95% CI.

FIG 2.

(A) Cumulative incidence of HF for three different treatment periods: 1960-1979 (No. = 11,456 cohort members and No. = 150 cases), 1980-1989 (No. = 12,660 cohort members and No. = 169 cases), and 1990-2008 (No. = 10,936 cohort members and No. = 66 cases). Pairwise comparisons showed these degrees of significance: 1960-1979 versus 1980-1989, P = .0004; 1960-1979 versus 1990-2008, P = .00008; 1980-1989 versus 1990-2008, P = .3917. (B) Cumulative incidence of cardiac mortality because of HF for three different treatment periods: 1960-1979 (No. = 11,456 cohort members and No. = 56 cases), 1980-1989 (No. = 12,660 cohort members and No. = 62 cases), and 1990-2008 (No. = 10,936 cohort members and No. = 9 cases). Pairwise comparisons showed these degrees of significance: 1960-1979 versus 1980-1989, P = .0001; 1960-1979 versus 1990-2008, P = .73; and 1980-1989 versus 1990-2008, P = .0005. HF, heart failure.

FIG 3.

(A) The ORs and corresponding 95% CIs (red dots and bars) of developing heart failure by the received total cumulative anthracycline dose and the fitted linear EOR and corresponding 95% CIs per 100 mg/m² anthracyclines (solid blue and gray line), both of which were adjusted for mean heart RT dose. ORs were calculated relative to survivors treated without anthracyclines and are plotted at the mean cumulative anthracyclines dose of the controls within each relevant dose category. (B) The ORs and corresponding 95% CIs (red dots and bars) of developing heart failure by the received mean heart RT dose and the fitted linear EOR and corresponding 95% CIs per 10 Gy mean heart RT (solid blue and gray line), both of which were adjusted for cumulative anthracycline dose. ORs were calculated relative to survivors treated without heart RT and are plotted at the mean cumulative radiation dose of the controls within each relevant dose category. EOR, excess odds ratio; OR, odds ratio; RT, radiation therapy.