In a Dutch study reported in JACC: CardioOncology, Jan M. Leerink, PhD candidate, of Amsterdam UMC, University of Amsterdam Department of Clinical and Experimental Cardiology, and colleagues found that the addition of ejection fraction measurement at the time of first surveillance echocardiogram improved prediction of 10-year risk of left-ventricular systolic dysfunction vs prediction based on cumulative anthracycline and chest-directed radiotherapy doses alone in long-term childhood cancer survivors.¹

As noted by the investigators, the current International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) guidelines recommend performance of echocardiograms once every 5 years to facilitate early detection and treatment of asymptomatic left-ventricular dysfunction in all childhood cancer survivors who received cardiotoxic cancer therapies.

Jan M. Leerink, PhD candidate

Study Details

The study involved measurement of ejection fraction at the time of first surveillance echocardiogram (initial ejection fraction) at more than 5 years after cancer diagnosis in a derivation cohort of 299 childhood cancer survivors from a site in Amsterdam (Emma Children’s Hospital) and a validation cohort of 218 childhood cancer survivors from a site in Nijmegen (Radboud University Medical Center). Childhood cancer survivors in both cohorts were aged 18 years or older at the first follow-up echocardiogram and had been treated with anthracyclines, mitoxantrone, and/or chest-directed radiotherapy. Participants with a history of heart failure before the first follow-up echocardiogram at least 5 years after cancer diagnosis and asymptomatic childhood cancer survivors with ejection fraction less than 40% before or at the first echocardiogram were excluded from both cohorts. In the derivation cohort, Cox regression models were constructed including cardiotoxic cancer treatment exposures with and without ejection fraction to estimate the probability developing left-ventricular dysfunction with an ejection fraction less than 40% (LVD40) at 10-year follow-up.

The cumulative incidence of LVD40 at 10-year follow-up in the entire cohort was 3.7%. The cumulative LVD40 incidence was 11.0% in childhood cancer survivors with midrange initial ejection fraction (40%–49%; 13% of childhood cancer survivors) vs 2.6% in those with preserved ejection fraction (≥ 50%; P = .012). In a multivariate analysis adjusted for anthracycline and chest-directed radiotherapy, childhood cancer survivors with midrange ejection fraction had a higher risk of LVD40 vs those with preserved ejection fraction (hazard ratio [HR] = 7.8; 95% confidence interval [CI] = 2.1–29.5). Lower ejection fraction was associated with an increased risk of LVD40 during follow-up at a hazard ratio of 9.6 (95% CI = 2.8–32.6) per 10-point ejection fraction decrease.

The addition of ejection fraction to the prediction model consisting of anthracycline and chest-directed radiotherapy dose increased the integrated AUC from 0.74 (bias = 0.018, 95% CI = 0.55–0.84) to 0.87 (bias = 0.009, 95% CI = 0.71–0.98). The likelihood ratio test comparing predictive performance of the model with vs without ejection fraction had a P value < .0001.

Assessment of continuous net reclassification improvement (cNRI), indicating the proportion of childhood cancer survivors with an accurate change in predicted risk using the model with vs without ejection fraction, showed no significant improvement in risk reclassification among LVD40 cases (cNRI = 0.15, 95% CI = –0.55 to 0.84) but significant improvement among childhood cancer survivors who did not develop LVD40 (cNRI = 0.50, 95% CI = 0.40–0.60). Based on the model including ejection fraction, 10-year predicted risk of LVD40 was ≤ 3% for 76.3% of childhood cancer survivors, with the model showing a sensitivity of 89.8%, a specificity of 76.2%, a negative predictive value of 99.5%, and a positive predictive value of 12.0%.

In the validation cohort, median age at cancer diagnosis was 7.02 years (25th–75th percentile = 4.00–12.46 years), median time from diagnosis to first follow-up echocardiogram was 16.95 years (25th–75th percentile = 12.99–21.70 years), and median age at first follow-up echocardiogram was 22.63 years (25th–75th percentile = 20.05–28.06 years). Median follow-up after first follow-up echocardiogram was 8.9 years (25th–75th percentile = 5.2–10.9 years). The cumulative incidence of LVD40 at 10-year follow-up was 3.6%.

For the model including ejection fraction vs the model including only anthracycline and radiotherapy dose, the integrated AUC increased from 0.72 (bias = –0.003, 95% CI = 0.70–0.77) to 0.86 (bias = –0.003, 95% CI = 0.83–0.89; likelihood ratio P < .001). Based on the model including ejection fraction, predicted 10-year probability of LVD40 was ≤ 3% in 74.8% of childhood cancer survivors.

Interaction With IGHG Risk Groups

Analysis of the predicted probabilities of 10-year LVD40 in individual childhood cancer survivors with different predictor value combinations using the ejection fraction–containing model showed that childhood cancer survivors in the low- and moderate-risk group according to IGHG surveillance guidelines with preserved initial ejection fraction (ejection fraction = 55%) had a predicted LVD40 probability of ≤ 3.0%. Childhood cancer survivors in the low- and moderate-risk groups with a midrange ejection fraction (ejection fraction = 48%) had a predicted LVD40 probability with an upper 95% CI of > 3.0%.

The prediction model including a surveillance ejection fraction, cumulative anthracycline, and chest-directed radiotherapy dose is available online at https://risk-of-cardiomyopathy.netlify.com/.

The investigators stated: “Our results demonstrate that [ejection fraction] measured with a surveillance echocardiogram at a median of 17 years … from cancer diagnosis and a median age of 23 years … has additional predictive value in the risk stratification for a therapeutically relevant decreased [ejection fraction] < 40%. Our validated model and 10-year risk calculator can be used to classify 75% of [childhood cancer survivors] as low risk for LVD40 within 10 years; less frequent surveillance may be appropriate in these survivors….”

They concluded: “In [childhood cancer survivors], an initial surveillance [ejection fraction], 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."

DISCLOSURE: Dr. Leerink reported no conflicts of interest.

REFERENCE

1. Leerink JM, van der Pal HJH, Kremer LCM, et al: Refining the 10-year prediction of left ventricular systolic dysfunction in long-term survivors of childhood cancer. JACC: CardioOncol 3:62-72, 2021.