A Biomarker-Based Diagnostic Model for Cardiac Dysfunction in Childhood Cancer Survivors.

Background: Childhood cancer survivors at risk for heart failure undergo lifelong echocardiographic surveillance. Previous studies reported the limited diagnostic accuracy of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) in detecting left ventricular (LV) dysfunction. However, potential enhanced diagnostic accuracy through the combination of biomarkers and clinical characteristics has been suggested. Objectives: The aim of this study was to develop and internally validate a diagnostic model that combines cardiac biomarkers with clinical characteristics for effectively ruling in or ruling out LV dysfunction in childhood cancer survivors. Methods: A multicenter cross-sectional study included 1,334 survivors (median age 34.2 years) and 278 siblings (median age 36.8 years). Logistic regression models were developed and validated through bootstrapping, combining biomarkers with clinical characteristics. Results: Abnormal NT-proBNP levels were observed in 22.1% of survivors compared with 5.4% of siblings, whereas hs-cTnT levels exceeding 10 ng/L were uncommon in both survivors (5.9%) and siblings (5.0%). The diagnostic models demonstrated improvement upon the addition of NT-proBNP and hs-cTnT to clinical characteristics, resulting in an increased C statistic from 0.69 to 0.73 for LV ejection fraction (LVEF) <50% and a more accurate prediction of more severe LV dysfunction, with the C statistic increasing from 0.80 to 0.86 for LVEF <45%. For LVEF <50% (prevalence 10.9%), 16.9% of survivors could be effectively ruled out with high sensitivity (95.4%; 95% CI: 90.4%-99.3%) and negative predictive value (97.5%; 95% CI: 94.6%-99.7%). Similarly, for LVEF <45% (prevalence 3.4%), 53.0% of survivors could be ruled out with moderate to high sensitivity (91.1%; 95% CI: 79.2%-100%) and high negative predictive value (99.4%; 95% CI: 98.7%-100%). Conclusions: The biomarker-based diagnostic model proves effective in ruling out LV dysfunction, offering the potential to minimize unnecessary surveillance echocardiography in childhood cancer survivors. External validation is essential to confirm these findings. (Early Detection of Cardiac Dysfunction in Childhood Cancer Survivors; A DCOG LATER Study; https://onderzoekmetmensen.nl/nl/trial/23641).

Presence and utility of electrocardiographic abnormalities in long-term childhood cancer survivors.

BACKGROUND: We assessed the prevalence and diagnostic value of ECG abnormalities for cardiomyopathy surveillance in childhood cancer survivors. METHODS: In this cross-sectional study, 1381 survivors (≥5 years) from the Dutch Childhood Cancer Survivor Study part 2 and 272 siblings underwent a long-term follow-up ECG and echocardiography. We compared ECG abnormality prevalences using the Minnesota Code between survivors and siblings, and within biplane left ventricular ejection fraction (LVEF) categories. Among 880 survivors who received anthracycline, mitoxantrone or heart radiotherapy, logistic regression models using least absolute shrinkage and selection operator identified ECG abnormalities associated with three abnormal LVEF categories (<52% in male/<54% in female, <50% and <45%). We assessed the overall contribution of these ECG abnormalities to clinical regression models predicting abnormal LVEF, assuming an absence of systolic dysfunction with a <1% threshold probability. RESULTS: 16% of survivors (52% female, mean age 34.7 years) and 14% of siblings had major ECG abnormalities. ECG abnormalities increased with decreasing LVEF. Integrating selected ECG data into the baseline model significantly improved prediction of sex-specific abnormal LVEF (c-statistic 0.66 vs 0.71), LVEF <50% (0.66 vs 0.76) and LVEF <45% (0.80 vs 0.86). While no survivor met the preset probability threshold in the first two models, the third model used five ECG variables to predict LVEF <45% and was applicable for ruling out (sensitivity 93%, specificity 56%, negative predictive value 99.6%). Calibration and internal validation tests performed well. CONCLUSION: A clinical prediction model with ECG data (left bundle branch block, left atrial enlargement, left heart axis, Cornell's criteria for left ventricular hypertrophy and heart rate) may aid in ruling out LVEF <45%.

Acute and early-onset cardiotoxicity in children and adolescents with cancer: a systematic review.

BACKGROUND: Cardiotoxicity is among the most important adverse effects of childhood cancer treatment. Anthracyclines, mitoxantrone and radiotherapy involving the heart are its main causes. Subclinical cardiac dysfunction may over time progress to clinical heart failure. The majority of previous studies have focused on late-onset cardiotoxicity. In this systematic review, we discuss the prevalence and risk factors for acute and early-onset cardiotoxicity in children and adolescents with cancer treated with anthracyclines, mitoxantrone or radiotherapy involving the heart. METHODS: A literature search was performed within PubMed and reference lists of relevant studies. Studies were eligible if they reported on cardiotoxicity measured by clinical, echocardiographic and biochemical parameters routinely used in clinical practice during or within one year after the start of cancer treatment in ≥ 25 children and adolescents with cancer. Information about study population, treatment, outcomes of diagnostic tests used for cardiotoxicity assessment and risk factors was extracted and risk of bias was assessed. RESULTS: Our PubMed search yielded 3649 unique publications, 44 of which fulfilled the inclusion criteria. One additional study was identified by scanning the reference lists of relevant studies. In these 45 studies, acute and early-onset cardiotoxicity was studied in 7797 children and adolescents. Definitions of acute and early-onset cardiotoxicity prove to be highly heterogeneous. Prevalence rates varied for different cardiotoxicity definitions: systolic dysfunction (0.0-56.4%), diastolic dysfunction (30.0-100%), combinations of echocardiography and/or clinical parameters (0.0-38.1%), clinical symptoms (0.0-25.5%) and biomarker levels (0.0-37.5%). Shortening fraction and ejection fraction significantly decreased during treatment. Cumulative anthracycline dose proves to be an important risk factor. CONCLUSIONS: Various definitions have been used to describe acute and early-onset cardiotoxicity due to childhood cancer treatment, complicating the establishment of its exact prevalence. Our findings underscore the importance of uniform international guidelines for the monitoring of cardiac function during and shortly after childhood cancer treatment.

Extensive Cardiac Function Analyses Using Contemporary Echocardiography in Childhood Cancer Survivors: A DCCSS LATER Study.

Background: Childhood cancer survivors (CCS) are at risk for cardiotoxicity. Objectives: We sought to assess how cardiac dysfunction measurements in CCS overlap and are differentially influenced by risk factors. Methods: This cross-sectional Dutch Childhood Cancer Survivor Study evaluated echocardiograms of 1,397 ≥5-year CCS and 277 siblings. Of CCS, n = 1,254 received cardiotoxic (anthracyclines/mitoxantrone/radiotherapy involving the heart region [RTheart]) and n = 143 received potentially cardiotoxic (cyclophosphamide, ifosfamide, or vincristine) therapy. We assessed demographic, treatment-related, and traditional cardiovascular risk factors for cardiac dysfunction using multivariable logistic regression. Results: CCS were a median of 26.7 years after diagnosis; 49% were women. Abnormal left ventricular ejection fraction (LVEF) (defined as <52% in men, <54% in women) occurred most commonly in CCS treated with anthracyclines and RTheart combined (38%). Age/sex-specific abnormal global longitudinal strain (GLS) occurred most commonly in CCS treated with RTheart, either with (41%) or without (38%) anthracyclines. Of CCS with normal LVEF, 20.2% showed abnormal GLS. Diastolic dysfunction grade ≥II was rare. Abnormal LVEF was mainly associated with female sex, anthracycline dose, and only in women, RTheart dose. Abnormal GLS was associated with female sex, RTheart dose, diastolic blood pressure, and only in women, anthracycline dose. Cyclophosphamide, ifosfamide, and vincristine were not associated with LVEF or GLS. Compared with siblings, CCS showed higher risk of abnormal LVEF (OR: 2.9; 95% CI: 1.4-6.6) and GLS (OR: 2.1; 95% CI: 1.2-3.7), independent of (potentially) cardiotoxic treatment-related and cardiovascular risk factors. Conclusions: Abnormal LVEF and GLS constitute complementary measures of systolic dysfunction among long-term CCS. Their diagnostic value may differ according to cardiotoxic exposures. Also, CCS have residual, unexplained risk of cardiac dysfunction. (Early Detection of Cardiac Dysfunction in Childhood Cancer Survivors, a DCOG LATER study; NTR7481).

Meta-epidemiological review identified variable reporting and handling of time-to-event analyses in publications of trials included in meta-analyses of systematic reviews.

OBJECTIVES: Previous findings indicate limited reporting of systematic reviews with meta-analyses of time-to-event (TTE) outcomes. We assessed corresponding available information in trial publications included in such meta-analyses. STUDY DESIGN AND SETTING: We extracted data from all randomized trials in pairwise, hazard ratio (HR)-based meta-analyses of primary outcomes and overall survival of 50 systematic reviews systematically identified from the Cochrane Database and Core Clinical Journals. Data on methods and characteristics relevant for TTE analysis of reviews, trials, and outcomes were extracted. RESULTS: Meta-analyses included 235 trials with 315 trial analyses. Most prominently assessed was overall survival (91%). Definitions (61%), censoring reasons (41%), and follow-up specifications (56%) for trial outcomes were often missing. Available TTE data per trial were most frequently survival curves (83%), log-rank P values (76%), and HRs (72%). When trial TTE data recalculation was reported, reviews mostly specified HRs or P values (each 5%). Reviews primarily included intention-to-treat analyses (64%) and analyses not adjusted for covariates (25%). Except for missing outcome data, TTE-relevant trial characteristics, for example, informative censoring, treatment switching, and proportional hazards, were sporadically addressed in trial publications. Reporting limitations in trial publications translate to the review level. CONCLUSION: TTE (meta)-analyses, in trial and review publications, need clear reporting standards.

GRADE concept 4: rating the certainty of evidence when study interventions or comparators differ from PICO targets.

OBJECTIVES: This Grading of Recommendations Assessment, Development and Evaluation (GRADE) concept article offers systematic reviewers, guideline authors, and other users of evidence assistance in addressing randomized trial situations in which interventions or comparators differ from those in the target people, interventions, comparators, and outcomes. To clarify what GRADE considers under indirectness of interventions and comparators, we focus on a particular example: when comparator arm participants receive some or all aspects of the intervention management strategy (treatment switching). STUDY DESIGN AND SETTING: An interdisciplinary panel of the GRADE working group members developed this concept article through an iterative review of examples in multiple teleconferences, small group sessions, and e-mail correspondence. After presentation at a GRADE working group meeting in November 2022, attendees approved the final concept paper, which we support with examples from systematic reviews and individual trials. RESULTS: In the presence of safeguards against risk of bias, trials provide unbiased estimates of the effect of an intervention on the people as enrolled, the interventions as implemented, the comparators as implemented, and the outcomes as measured. Within the GRADE framework, differences in the people, interventions, comparators, and outcomes elements between the review or guideline recommendation targets and the trials as implemented constitute issues of indirectness. The intervention or comparator group management strategy as implemented, when it differs from the target comparator, constitutes one potential source of indirectness: Indirectness of interventions and comparators-comparator group receipt of the intervention constitutes a specific subcategory of said indirectness. The proportion of comparator arm participants that received the intervention and the apparent magnitude of effect bear on whether one should rate down, and if one does, to what extent. CONCLUSION: Treatment switching and other differences between review or guideline recommendation target interventions and comparators vs. interventions and comparators as implemented in otherwise relevant trials are best considered issues of indirectness.

Safety of Growth Hormone Replacement Therapy in Childhood-Onset Craniopharyngioma: A Systematic Review and Cohort Study.

INTRODUCTION: Survival of childhood-onset craniopharyngioma (cCP) is excellent; however, many survivors suffer from hypothalamic-pituitary dysfunction. Growth hormone replacement therapy (GHRT) is of high importance for linear growth and metabolic outcome. Optimal timing for initiation of GHRT in cCP is on debate because of concerns regarding tumor progression or recurrence. METHODS: A systematic review and cohort studys were performed for the effect and timing of GHRT on overall mortality, tumor progression/recurrence, and secondary tumors in cCP. Within the cohort, cCP receiving GHRT ≤1 year after diagnosis were compared to those receiving GHRT >1 year after diagnosis. RESULTS: Evidence of 18 included studies, reporting on 6,603 cCP with GHRT, suggests that GHRT does not increase the risk for overall mortality, progression, or recurrent disease. One study evaluated timing of GHRT and progression/recurrence-free survival and found no increased risk with earlier initiation. One study reported a higher than expected prevalence of secondary intracranial tumors compared to a healthy population, possibly confounded by radiotherapy. In our cohort, 75 of 87 cCP (86.2%) received GHRT for median of 4.9 years [0.0-17.1]. No effect of timing of GHRT was found on mortality, progression/recurrence-free survival, or secondary tumors. CONCLUSION: Although the quality of the evidence is low, the available evidence suggests no effect of GHRT or its timing on mortality, tumor progression/recurrence, or secondary neoplasms in cCP. These results support early initiation of GHRT in cCP aiming to optimize linear growth and metabolic outcome. Prospective studies are needed to increase the level of evidence upon the optimal timing to start GHRT in cCP patients.

Positive and negative survivor-specific psychosocial consequences of childhood cancer: the DCCSS-LATER 2 psycho-oncology study.

PURPOSE: Numerous studies investigated generic psychosocial outcomes in survivors of childhood cancer (CCS). The present study aimed to describe survivor-specific psychosocial consequences in CCS, and to identify socio-demographic and medical associated factors. METHODS: CCS from the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER cohort (diagnosed 1963-2001) part 2 (age ≥ 18 years, diagnosed < 18 years, ≥ 5 years since diagnosis) completed the Benefit & Burden Scale (BBSC) and the Impact of Cancer-Childhood Cancer (IOC-CS). Items were scored on a 5-point Likert scale (range 1-5). We examined outcomes with descriptive statistics, and socio-demographic and medical associated factors with regression analyses, corrected for multiple testing (p < 0.004). RESULTS: CCS, N = 1713, age mean (M) 36 years, 49% female, ≥ 15 years since diagnosis, participated. On average, CCS reported 'somewhat' Benefit (M = 2.9), and 'not at all' to 'a little' Burden (M = 1.5) of childhood cancer. Average scores on IOC-CS' positive impact scales ranged from 2.5 (Personal Growth) to 4.1 (Socializing), and on the negative impact scales from 1.4 (Financial Problems) to 2.4 (Thinking/Memory). Apart from cognitive problems, CCS reported challenges as worries about relationship status, fertility, and how cancer had affected siblings. Female sex was associated with more Personal Growth, and more negative impact. CCS more highly educated, partnered, and employed had higher positive and lower negative impact. CCS older at diagnosis reported more positive impact. CNS tumor survivors and those who had head/cranium radiotherapy had higher negative impact. CNS tumor survivors reported less positive impact. CONCLUSION AND IMPLICATIONS: The majority of CCS reported positive impact of cancer while most CCS reported little negative impact. While this may indicate resiliency in most CCS, health care providers should be aware that they can also experience survivor-specific challenges that warrant monitoring/screening, information provision and psychosocial support.

Systematic review and updated recommendations for cardiomyopathy surveillance for survivors of childhood, adolescent, and young adult cancer from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Survivors of childhood, adolescent, and young adult cancer, previously treated with anthracycline chemotherapy (including mitoxantrone) or radiotherapy in which the heart was exposed, are at increased risk of cardiomyopathy. Symptomatic cardiomyopathy is typically preceded by a series of gradually progressive, asymptomatic changes in structure and function of the heart that can be ameliorated with treatment, prompting specialist organisations to endorse guidelines on cardiac surveillance in at-risk survivors of cancer. In 2015, the International Late Effects of Childhood Cancer Guideline Harmonization Group compiled these guidelines into a uniform set of recommendations applicable to a broad spectrum of clinical environments with varying resource availabilities. Since then, additional studies have provided insight into dose thresholds associated with a risk of asymptomatic and symptomatic cardiomyopathy, have characterised risk over time, and have established the cost-effectiveness of different surveillance strategies. This systematic Review and guideline provides updated recommendations based on the evidence published up to September, 2020.

Thyroid dysfunction during treatment with systemic antineoplastic therapy for childhood cancer: A systematic review.

Thyroid dysfunction is known to occur following radiotherapy or chemotherapy for childhood cancer. Thyroid dysfunction during treatment for childhood cancer has, however, not been studied extensively, although thyroid hormones are of utmost importance during childhood. This information is needed to develop adequate screening protocols and may be of special importance with upcoming drugs, such as checkpoint inhibitors, which are highly associated with thyroid dysfunction in adults. In this systematic review we have evaluated the occurrence and risk factors for thyroid dysfunction in children during treatment with systemic antineoplastic drugs, up to three months after the end of therapy. Two review authors independently performed the study selection, data extraction and risk of bias assessment of included studies. After an extensive search (January 2021), in total six heterogeneous articles were included, reporting on 91 childhood cancer patients with a thyroid function test during treatment with systemic antineoplastic therapy for childhood cancer. All studies had risk of bias issues. Primary hypothyroidism was found in 18% of children treated with high dose interferon-α (HDI-α) and in 0-10% after tyrosine kinase inhibitors (TKIs). Transient euthyroid sick syndrome (ESS) was common (in 42-100%) during treatment with systematic multi-agent chemotherapy. Only one study addressed possible risk factors, showing different types of treatment to increase the risk. However, the exact prevalence, risk factors and clinical consequences of thyroid dysfunction remain unclear. Prospective high-quality studies including large study samples are needed to longitudinally assess the prevalence, risk factors and possible consequences of thyroid dysfunction during childhood cancer treatment.

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

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.

Primary cardioprotection with dexrazoxane in patients with childhood cancer who are expected to receive anthracyclines: recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Survivors of childhood cancer are at risk of anthracycline-induced cardiotoxicity, which might be prevented by dexrazoxane. However, concerns exist about the safety of dexrazoxane, and little guidance is available on its use in children. To facilitate global consensus, a working group within the International Late Effects of Childhood Cancer Guideline Harmonization Group reviewed the existing literature and used evidence-based methodology to develop a guideline for dexrazoxane administration in children with cancer who are expected to receive anthracyclines. Recommendations were made in consideration of evidence supporting the balance of potential benefits and harms, and clinical judgement by the expert panel. Given the dose-dependent risk of anthracycline-induced cardiotoxicity, we concluded that the benefits of dexrazoxane probably outweigh the risk of subsequent neoplasms when the cumulative doxorubicin or equivalent dose is at least 250 mg/m2 (moderate recommendation). No recommendation could be formulated for cumulative doxorubicin or equivalent doses of lower than 250 mg/m2, due to insufficient evidence to determine whether the risk of cardiotoxicity outweighs the possible risk of subsequent neoplasms. Further research is encouraged to determine the long-term efficacy and safety of dexrazoxane in children with cancer.

Dexrazoxane for preventing or reducing cardiotoxicity in adults and children with cancer receiving anthracyclines.

BACKGROUND: This review is the third update of a previously published Cochrane Review. The original review, looking at all possible cardioprotective agents, was split and this part now focuses on dexrazoxane only. Anthracyclines are effective chemotherapeutic agents in the treatment of numerous malignancies. Unfortunately, their use is limited by a dose-dependent cardiotoxicity. In an effort to prevent or reduce this cardiotoxicity, different cardioprotective agents have been studied, including dexrazoxane. OBJECTIVES: To assess the efficacy of dexrazoxane to prevent or reduce cardiotoxicity and determine possible effects of dexrazoxane on antitumour efficacy, quality of life and toxicities other than cardiac damage in adults and children with cancer receiving anthracyclines when compared to placebo or no additional treatment. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase to May 2021. We also handsearched reference lists, the proceedings of relevant conferences and ongoing trials registers. SELECTION CRITERIA: Randomised controlled trials (RCTs) in which dexrazoxane was compared to no additional therapy or placebo in adults and children with cancer receiving anthracyclines. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, data extraction, risk of bias and GRADE assessment of included studies. We analysed results in adults and children separately. We performed analyses according to the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: For this update, we identified 548 unique records. We included three additional RCTs: two paediatric and one adult. Therefore, we included a total of 13 eligible RCTs (five paediatric and eight adult). The studies enrolled 1252 children with leukaemia, lymphoma or a solid tumour and 1269 participants, who were mostly diagnosed with breast cancer. In adults, moderate-quality evidence showed that there was less clinical heart failure with the use of dexrazoxane (risk ratio (RR) 0.22, 95% confidence interval (CI) 0.11 to 0.43; 7 studies, 1221 adults). In children, we identified no difference in clinical heart failure risk between treatment groups (RR 0.20, 95% CI 0.01 to 4.19; 3 studies, 885 children; low-quality evidence). In three paediatric studies assessing cardiomyopathy/heart failure as the primary cause of death, none of the children had this outcome (1008 children, low-quality evidence). In the adult studies, different definitions for subclinical myocardial dysfunction and clinical heart failure combined were used, but pooled analyses were possible: there was a benefit in favour of the use of dexrazoxane (RR 0.37, 95% CI 0.24 to 0.56; 3 studies, 417 adults and RR 0.46, 95% CI 0.33 to 0.66; 2 studies, 534 adults, respectively, moderate-quality evidence). In the paediatric studies, definitions of subclinical myocardial dysfunction and clinical heart failure combined were incomparable, making pooling impossible. One paediatric study showed a benefit in favour of dexrazoxane (RR 0.33, 95% CI 0.13 to 0.85; 33 children; low-quality evidence), whereas another study showed no difference between treatment groups (Fischer exact P = 0.12; 537 children; very low-quality evidence). Overall survival (OS) was reported in adults and overall mortality in children. The meta-analyses of both outcomes showed no difference between treatment groups (hazard ratio (HR) 1.04, 95% 0.88 to 1.23; 4 studies; moderate-quality evidence; and HR 1.01, 95% CI 0.72 to 1.42; 3 studies, 1008 children; low-quality evidence, respectively). Progression-free survival (PFS) was only reported in adults. We subdivided PFS into three analyses based on the comparability of definitions, and identified a longer PFS in favour of dexrazoxane in one study (HR 0.62, 95% CI 0.43 to 0.90; 164 adults; low-quality evidence). There was no difference between treatment groups in the other two analyses (HR 0.95, 95% CI 0.64 to 1.40; 1 study; low-quality evidence; and HR 1.18, 95% CI 0.97 to 1.43; 2 studies; moderate-quality evidence, respectively). In adults, there was no difference in tumour response rate between treatment groups (RR 0.91, 95% CI 0.79 to 1.04; 6 studies, 956 adults; moderate-quality evidence). We subdivided tumour response rate in children into two analyses based on the comparability of definitions, and identified no difference between treatment groups (RR 1.01, 95% CI 0.95 to 1.07; 1 study, 206 children; very low-quality evidence; and RR 0.92, 95% CI 0.84 to 1.01; 1 study, 200 children; low-quality evidence, respectively). The occurrence of secondary malignant neoplasms (SMN) was only assessed in children. The available and worst-case analyses were identical and showed a difference in favour of the control group (RR 3.08, 95% CI 1.13 to 8.38; 3 studies, 1015 children; low-quality evidence). In the best-case analysis, the direction of effect was the same, but there was no difference between treatment groups (RR 2.51, 95% CI 0.96 to 6.53; 4 studies, 1220 children; low-quality evidence). For other adverse effects, results also varied. None of the studies evaluated quality of life. If not reported, the number of participants for an analysis was unclear. AUTHORS' CONCLUSIONS: Our meta-analyses showed the efficacy of dexrazoxane in preventing or reducing cardiotoxicity in adults treated with anthracyclines. In children, there was a difference between treatment groups for one cardiac outcome (i.e. for one of the definitions used for clinical heart failure and subclinical myocardial dysfunction combined) in favour of dexrazoxane. In adults, no evidence of a negative effect on tumour response rate, OS and PFS was identified; and in children, no evidence of a negative effect on tumour response rate and overall mortality was identified. The results for adverse effects varied. In children, dexrazoxane may be associated with a higher risk of SMN; in adults this was not addressed. In adults, the quality of the evidence ranged between moderate and low; in children, it ranged between low and very low. Before definitive conclusions on the use of dexrazoxane can be made, especially in children, more high-quality research is needed. We conclude that if the risk of cardiac damage is expected to be high, it might be justified to use dexrazoxane in children and adults with cancer who are treated with anthracyclines. However, clinicians and patients should weigh the cardioprotective effect of dexrazoxane against the possible risk of adverse effects, including SMN, for each individual. For children, the International Late Effects of Childhood Cancer Guideline Harmonization Group has developed a clinical practice guideline.

Cardiac function in childhood cancer survivors treated with vincristine: Echocardiographic results from the DCCSS LATER 2 CARD study.

BACKGROUND: Anthracyclines and radiotherapy involving the heart region are cardiotoxic, but the potential cardiotoxicity of vincristine remains unknown. We assessed cardiac function in vincristine-treated >5-year childhood cancer survivors (CCS). METHODS AND RESULTS: We cross-sectionally compared echocardiograms of 101 vincristine-treated CCS (median age 35 years [range: 17-53], median vincristine dose 63 mg/m2) from the national Dutch Childhood Cancer Survivor Study, LATER cohort, to 101 age- and sex-matched controls. CCS treated with anthracyclines, radiotherapy involving the heart region, cyclophosphamide or ifosfamide were excluded. Twelve CCS (14%) versus four controls (4%; p 0.034) had a decreased left ventricular ejection fraction (LVEF; men <52%, women <54%). Mean LVEF was 58.4% versus 59.7% (p 0.050). Global longitudinal strain (GLS) was abnormal in nineteen (24%) CCS versus eight controls (9%; p 0.011). Mean GLS was 19.0% versus 20.1% (p 0.001). No ≥grade 2 diastolic dysfunction was detected. In multivariable logistic regression analysis CCS had higher risk of abnormal GLS (OR 3.55, p 0.012), but not abnormal LVEF (OR 3.07, p 0.065), than controls. Blood pressure and smoking history contributed to variation in LVEF, whereas obesity and diastolic blood pressure contributed to variation in GLS. Cumulative vincristine dose was not associated with either abnormal LVEF or abnormal GLS in multivariable models corrected for age and sex (OR per 50 mg/m2: 0.88, p 0.85 and 1.14, p 0.82, respectively). CONCLUSIONS: Vincristine-treated long-term CCS showed an abnormal GLS more frequently than controls. Their risk for future clinical cardiac events and the role of risk factor modification should be further elucidated.

Candidate Plasma Biomarkers to Detect Anthracycline-Related Cardiomyopathy in Childhood Cancer Survivors: A Case Control Study in the Dutch Childhood Cancer Survivor Study.

Background Plasma biomarkers may aid in the detection of anthracycline-related cardiomyopathy (ACMP). However, the currently available biomarkers have limited diagnostic value in long-term childhood cancer survivors. This study sought to identify diagnostic plasma biomarkers for ACMP in childhood cancer survivors. Methods and Results We measured 275 plasma proteins in 28 ACMP cases with left ventricular ejection fraction <45%, 29 anthracycline-treated controls with left ventricular ejection fraction ≥53% matched on sex, time after cancer, and anthracycline dose, and 29 patients with genetically determined dilated cardiomyopathy with left ventricular ejection fraction <45%. Multivariable linear regression was used to identify differentially expressed proteins. Elastic net model, including clinical characteristics, was used to assess discrimination of proteins diagnostic for ACMP. NT-proBNP (N-terminal pro-B-type natriuretic peptide) and the inflammatory markers CCL19 (C-C motif chemokine ligands 19) and CCL20, PSPD (pulmonary surfactant protein-D), and PTN (pleiotrophin) were significantly upregulated in ACMP compared with controls. An elastic net model selected 45 proteins, including NT-proBNP, CCL19, CCL20 and PSPD, but not PTN, that discriminated ACMP cases from controls with an area under the receiver operating characteristic curve (AUC) of 0.78. This model was not superior to a model including NT-proBNP and clinical characteristics (AUC=0.75; P=0.766). However, when excluding 8 ACMP cases with heart failure, the full model was superior to that including only NT-proBNP and clinical characteristics (AUC=0.75 versus AUC=0.50; P=0.022). The same 45 proteins also showed good discrimination between dilated cardiomyopathy and controls (AUC=0.89), underscoring their association with cardiomyopathy. Conclusions We identified 3 specific inflammatory proteins as candidate plasma biomarkers for ACMP in long-term childhood cancer survivors and demonstrated protein overlap with dilated cardiomyopathy.

Late Toxicity After 3-Dimensional External Beam Radiotherapy Among Children With Cancer: A Systematic Review.

Radiotherapy has evolved from 2-dimensional conventional radiotherapy (2D-RT) to 3-dimensional planned radiotherapy (3D-RT). Because 3D-RT improves conformity, an altered late health outcomes risk profile is anticipated. Here, we systematically reviewed the current literature on late toxicity after 3D-RT in children treated for cancer. PubMed was searched for studies describing late toxicity after 3D-RT for childhood cancer (below 21 y). Late toxicity was defined as somatic health outcomes occurring ≥90 days after treatment. We identified 13 eligible studies, describing most frequently head/neck area tumors. Included studies reported on crude frequencies of late toxicities including subsequent tumors and conditions of organ systems. Three studies offered a global assessment of the full spectrum of late toxicity; one study compared toxicities after 2D-RT and 3D-RT. Incidence rates were typically not provided. Heterogeneity in study characteristics, small study sizes and short follow-up times precluded multivariable modeling and pooling of data. In conclusion, among the first pediatric cohorts treated with 3D-RT, a broad variety of late toxicity is reported; precise estimates of incidence, and contributions of risk factors are unclear. Continued systematic evaluation of well-defined health outcomes in survivors treated with 3D-RT, including proton therapy, is needed to optimize evidence-based care for children with cancer and survivors.

Electrocardiographic abnormalities in childhood cancer survivors treated with cardiotoxic therapy: a systematic review.

PURPOSE: The purpose of this study is to assess the available literature on the prevalence and risk factors of electrocardiographic (ECG) abnormalities after cardiotoxic treatment in childhood cancer survivors (CCS). METHODS: A literature search was performed within MEDLINE, EMBASE, and CENTRAL (1966-11/2020) and reference lists of relevant studies. Studies were eligible for inclusion if they reported ECG abnormalities ≥2 years after cancer diagnosis in ≥50 CCS treated with anthracyclines, RT involving the heart region and/or mitoxantrone. Information about population, treatment, outcome, and risk factors were extracted and risk of bias was assessed. RESULTS: Of 934 identified publications, 10 studies were included. Outcome definitions, treatment regimens, follow-up period, and risk of bias varied. These ECG abnormalities and prevalences were reported: major (5%-23%) and minor (12%) abnormalities according to the Minnesota Code, rhythm abnormalities (0%-12%), conduction abnormalities (0.3%-7.1%), depolarization abnormalities (0%), and repolarization abnormalities (0%-65%). The reported risk factors of ECG abnormalities (two studies) are male sex, anthracyclines, RT involving the heart region, and hypertension, although results were not univocal between studies and abnormalities. CONCLUSIONS: Multiple ECG abnormalities have been described in CCS ≥2 years from diagnosis, some of which can have important implications. Future research is needed to evaluate the exact long-term incidence and risk factors, and to investigate their clinical relevance and relation with cardiac dysfunction or future cardiac events. This could improve cardiac surveillance for CCS.

Neuroblastoma survivors at risk for developing subsequent neoplasms: A systematic review.

Neuroblastoma survivors have an increased risk of unfavorable long-term health outcomes, of which developing subsequent neoplasms is one of the most serious. We aimed to provide an overview of the current knowledge on the risk of subsequent neoplasms in neuroblastoma survivors. We conducted a systematic literature search in Medline/Pubmed (01-01-1945-13-01-2022) to identify studies that reported on ≥ 100 neuroblastoma survivors and assessed subsequent neoplasms as an outcome. We identified 410 potentially eligible articles, of which we eventually included 13 reports. All articles described retrospective cohorts with sizes varying from 145 to 5,987 neuroblastoma survivors. Within these cohorts 0.7% - 17.2% of the survivors developed a subsequent neoplasm. A wide variety of types of subsequent malignant and non-malignant neoplasms were observed, of which thyroid carcinoma and acute myeloid leukemia were most frequently reported. The risk of developing a subsequent neoplasm was 2.8 to 10.4 times higher in neuroblastoma survivors than in the general population. Although no statistically significant risk factors for subsequent neoplasms were observed in multivariable analyses, high-risk group survivors, women and those treated with radiotherapy seemed to have a higher risk. In conclusion, the studies in this systematic review consistently show that neuroblastoma survivors are at elevated risk of developing subsequent neoplasms. Future research should further explore risk factors for subsequent neoplasms in neuroblastoma survivors, so future treatment protocols and follow-up care can be improved.