Deciphering therapy-related cardiac damage and late effects in pediatric cancer survivors

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Abstract Background More than 80% of children treated for cancer survive. However, all-cause mortality of childhood cancer survivors remains increased at least 10-fold compared to the general population. Especially, the risk of death is increased by excessive cardiac and pulmonary disease as well as secondary cancers and relapse. Little is known about the individual sensitivity to develop cardiac toxicity and organ-specific late effects. Aim This study aims to characterize the most extensive German pediatric cancer survivorship cohort located at a tertiary care center with focus on cardiooncologic complications. Furthermore, we aim to identify potential markers of therapy-related toxicity and late effects by combining clinical data with a planned large-scale proteomics analysis. Materials & Methods Children and adolescents with cancer diagnosis between 01/08 and 12/15, who consented to participation in the local biobank study before the start of anti-neoplastic treatment were screened. Clinical and routine laboratory data were collected from patients´ electronic health records. Children were divided according to occurrence of a cardiovascular complication during or after the anti-neoplastic therapy. CV complications are defined as reduction of the LVEF>10% compared to the baseline or below 55% and/or one of the following: elevation of cardiac biomarkers (hs-TroponinT and/or proBNP), relevant elongation of the PQ/QRS/cQT-interval, newly diagnosed arterial hypertension, new T-inversion,new cardiac hypertrophy, pulmonary hypertension. Results & Conclusion 383 children were screened and 265 children were included in this analysis. Median follow up was 10 years (SD: 3,8). Approx. 60% of the children were male in both groups. 25% of the cohort developed some form of CV-complication during the anti-neoplastic therapy and an additional 25% during the follow up period (e.g.: LVEF reduction: 34%, arterial hypertension: 5.7%, QRS-elongation: 5.3%). Clinically relevant decrease of the LV-EF, defined as LVEF under 55% was observed by 8 patients after anti-neoplastic treatment which only persisted in 3 patients after completion of the follow-up. Children in the CV-complications group were significantly older at cancer diagnosis than patients without CV-complication (mean [SD] 9.6 [5.4] years vs. 7.9 [5.2]). Children in the CV-complication group had more frequently multiple CV-risk factors before cancer-therapy initiation compared to the no complication group (p<0.001) while there was no difference in the frequency of previous CV-disorders (p=0.637). Among the systemically used anti-neoplastic agents, only anthracylines showed a significant dose-dependent association with the occurrence of CV complications. CV-complications are common side effects of the anti-neoplastic therapy in children which needs to be addressed more precisely in the future. CV risk-evaluation and optimal medical therapy before anti-neoplastic therapy may reduce the complication burden.

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