Risk and Temporal Changes of Heart Failure Among 5-Year Childhood Cancer Survivors: a DCOG-LATER Study

Abstract

Background Heart failure is one of the most important late effects after treatment for cancer in childhood. The goals of this study were to evaluate the risk of heart failure, temporal changes by treatment periods, and the risk factors for heart failure in childhood cancer survivors ( CCS ). Methods and Results The DCOG-LATER (Dutch Childhood Oncology Group-Long-Term Effects After Childhood Cancer) cohort includes 6,165 5-year CCS diagnosed between 1963 and 2002. Details on prior cancer diagnosis and treatment were collected for this nationwide cohort. Cause-specific cumulative incidences and risk factors of heart failure were obtained. Cardiac follow-up was complete for 5,845 CCS (94.8%). After a median follow-up of 19.8 years and at a median attained age of 27.3 years, 116 survivors developed symptomatic heart failure. The cumulative incidence of developing heart failure 40 years after childhood cancer diagnosis was 4.4% (3.4%-5.5%) among all CCS. The cumulative incidence of heart failure grade ≥3 among survivors treated in the more recent treatment periods was higher compared with survivors treated earlier (Gray test, P=0.05). Mortality due to heart failure decreased in the more recent treatment periods (Gray test, P=0.02). In multivariable analysis, survivors treated with a higher dose of mitoxantrone or cyclophosphamide had a higher risk of heart failure than survivors who were exposed to lower doses. Conclusions CCS treated with mitoxantrone, cyclophosphamide, anthracyclines, or radiotherapy involving the heart are at a high risk for severe, life-threatening or fatal heart failure at a young age. Although mortality decreased, the incidence of severe or life-threatening heart failure increased with more recent treatment periods.

Keywords: childhood cancer survivors; heart failure.

Figure 1

Cumulative incidence of heart failure for cardiotoxic treatment (anthracyclines, mitoxantrone, and radiotherapy involving the heart) with time since childhood cancer diagnosis as time scale. P‐value for Gray test is P<0.0001. Shaded areas indicate 95% CI.

Figure 2

Cumulative incidence of heart failure (grades 3, 4, and 5) for 2 specific treatment groups: anthracyclines only (n=2598 cohort members, 96 cases) and mitoxantrone (with/without anthracyclines) (n=146 cohort members, 12 cases). All childhood cancer survivors who had radiotherapy involving the heart region were excluded from these analyses. Parwise comparisons found these degrees of significance: no anthracycline/mitoxantrone vs anthracycline 1 to 100 mg/m², P=0.17; no anthracycline/mitoxantrone vs anthracycline 100 to 250 mg/m², P<0.00001; no anthracycline/mitoxantrone vs anthracycline >250 mg/m², P<0.00001; no anthracycline/mitoxantrone vs mitoxantrone, P<0.00001; anthracycline 1 to 100 mg/m² vs anthracycline 100 to 250 mg/m², P=0.007; anthracycline 1 to 100 mg/m² vs anthracycline >250 mg/m², P<0.00001; anthracycline 1 to 100 mg/m² vs mitoxantrone, P<0.00001; anthracycline 100 to 250 mg/m² vs anthracycline >250 mg/m², P<0.00001; anthracycline 100 to 250 mg/m² vs mitoxantrone, P<0.00001; anthracycline >250 mg/m² vs mitoxantrone, P=0.02. Shaded areas indicate 95% CI.

Figure 3

A, Cumulative incidence of heart failure (grades 3, 4, and 5) per treatment period, with time since childhood cancer diagnosis. P‐value for Gray test: 1970–1979 vs 1980–1989, P=0.011; 1970–1979 vs 1990–2001, P=0.03; 1980–1989 vs 1990–2001, P=0.81 B, Cumulative incidence of heart failure grade 5, fatal events, per treatment period with time since childhood cancer diagnosis. P‐value for Gray test: 1970–1979 vs 1980–1989, P=0.99; 1970–1979 vs 1990–2001, P=0.04; 1980–1989 vs 1990–2001, P=0.02. All childhood cancer survivors diagnosed between 1970 and 2001 were included in this figure.

Figure 4

Dose‐response curves of the development of heart failure with anthracyclines, mitoxantrone, and cyclophosphamide. The colored triangles are the hazard ratios (HRs) from the model presented on a logarithmic scale to show the actual HRs. The model is also corrected for sex, age at diagnosis, year of childhood cancer diagnosis, and radiotherapy where the heart was in the field yes/no. Shaded areas indicate 95% CI.