Refining the 10-Year Prediction of Left Ventricular Systolic Dysfunction in Long-Term Survivors of Childhood Cancer

Abstract

Background: In childhood cancer survivors (CCS) at risk for heart failure, echocardiographic surveillance recommendations are currently based on anthracyclines and chest-directed radiotherapy dose. Whether the ejection fraction (EF) measured at an initial surveillance echocardiogram can refine these recommendations is unknown.

Objectives: The purpose of this study was to assess the added predictive value of EF at >5 years after cancer diagnosis to anthracyclines and chest-directed radiotherapy dose in CCS, for the development of left ventricular dysfunction with an ejection fraction <40% (LVD40).

Methods: Echocardiographic surveillance was performed in 299 CCS from the Emma Children's Hospital in the Netherlands. Cox regression models were built including cardiotoxic cancer treatment exposures with and without EF to estimate the probability of LVD40 at 10-year follow-up. Calibration, discrimination, and reclassification were assessed. Results were externally validated in 218 CCS.

Results: Cumulative incidences of LVD40 at 10-year follow-up were 3.7% and 3.6% in the derivation and validation cohort, respectively. The addition of EF resulted in an integrated area under the curve increase from 0.74 to 0.87 in the derivation cohort and from 0.72 to 0.86 in the validation cohort (likelihood ratio p < 0.001). Reclassification of CCS without LVD40 improved significantly (noncase continuous net reclassification improvement 0.50; 95% confidence interval [CI]: 0.40 to 0.60). A predicted LVD40 probability ≤3%, representing 75% of the CCS, had a negative predictive value of 99% (95% CI: 98% to 100%) for LVD40 within 10 years. However, patients with midrange EF (40% to 49%) at initial screening had an incidence of LVD40 of 11% and a 7.81-fold (95% CI: 2.07- to 29.50-fold) increased risk of LV40 at follow-up.

Conclusions: In CCS, an initial surveillance EF, in addition to anthracyclines and chest-directed radiotherapy dose, improves the 10-year prediction for LVD40. Through this strategy, both the identification of low-risk survivors in whom the surveillance frequency may be reduced and a group of survivors at increased risk of LVD40 could be identified.

Keywords: CCS, childhood cancer survivors; CI, confidence interval; EF, ejection fraction; LVD40, left ventricular dysfunction with an ejection fraction <40%; cardio-oncology; childhood cancer survivors; echocardiography; risk prediction model; surveillance.

Graphical abstract

Figure 1

Flowchart of Patient Inclusion Flowchart describing the inclusion of childhood cancer survivors (CCS) in the derivation and validation cohort. Adult survivors who were previously treated with cardiotoxic cancer treatments with at least 2 surveillance echocardiograms performed at more than 5 years from cancer diagnosis and with <5 years between each echocardiogram were selected. Survivors with heart failure or an ejection fraction <40% before or at the first surveillance echocardiogram were excluded. echo = echocardiogram; EKZ = Emma Children’s Hospital; Radboud = Radboud University Medical Center.

Figure 2

Calibration Plots Agreement between the predicted 10-year probabilities of a left ventricular ejection fraction <40% (LVD40) obtained from the Cox regression model compared with the observed 10-year LVD40 probabilities in the derivation and the validation cohorts. Predictions from the final multivariable Cox regression model including ejection fraction are shown.

Central Illustration

Refinement of the IGHG Surveillance Guideline Risk Groups Using the EF Measured With a Surveillance Echocardiogram Predicted probabilities for developing left ventricular dysfunction with ejection fraction (EF) <40% within 10 years in individual fictional survivors. In colors the risk categories (low, moderate, or high) are presented according to the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG). In each IGHG risk category, the 10-year probability of left ventricular dysfunction with EF <40% is compared between a survivor with an initial surveillance EF of 48% and a survivor with an initial EF of 55%. Bars represent the risk estimate; error bars represent the 95% confidence interval.