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Background: Childhood cancer survivors (CCS) are a growing group of young individuals with a high risk of morbidity and mortality. We evaluated the prevalence and risk factors of hepatic late adverse effects, defined as elevated liver enzymes, in a large cohort of CCS., Methods: The cohort consisted of all five-year CCS treated in the EKZ/AMC between 1966 and 2003, without hepatitis virus infection and history of veno-occlusive disease (VOD). Liver enzyme tests included serum levels of alanine aminotransferase (ALT) for hepatocellular injury and gamma-glutamyltransferase (γGT) for biliary tract injury. We performed multivariable linear and logistic regression analyses., Results: The study population consisted of 1404 of 1795 eligible CCS, of whom 1362 performed liver enzyme tests at a median follow-up of 12 years after diagnosis. In total, 118 (8.7%) of 1362 CCS had hepatic late adverse effects defined as ALT or γGT above the upper limit of normal. Abnormal ALT and γGT levels were found in 5.8% and 5.3%, respectively. In multivariable regression analyses treatment with radiotherapy involving the liver, higher body mass index, higher alcohol intake and longer follow-up time were significantly associated with elevated ALT and γGT levels; older age at diagnosis was only significantly associated with elevated γGT levels (all p<0.05)., Conclusion: One in twelve CCS showed signs of hepatic late adverse effects after a median follow-up of 12 years. Several risk factors have been identified. Future studies should focus on the course of long-term liver related outcomes and on the influence of radiotherapy and chemotherapy dose., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Childhood cancer survivors (CCSs) have an increased risk of morbidity and mortality. We evaluated the prevalence and determinants of left ventricular (LV) dysfunction in a large cohort of long-term CCSs treated with different potentially cardiotoxic therapies., Methods: The study cohort consisted of all adult 5-year CCSs who were treated with potentially cardiotoxic therapies and who visited our late effects outpatient clinic. Echocardiography was performed in patients who had received anthracyclines, cardiac irradiation, high-dose cyclophosphamide, or high-dose ifosfamide. Detailed treatment data were registered. Both multivariate linear and logistic regression analyses were performed., Results: Of 601 eligible CCSs, 525 (87%) had an echocardiogram performed, of which 514 were evaluable for assessment of the LV shortening fraction (LVSF). The median overall LVSF in the whole group of CCSs was 33.1% (range, 13.0%-56.0%). Subclinical cardiac dysfunction (LVSF <30%) was identified in 139 patients (27%). In a multivariate linear regression model, LVSF was reduced with younger age at diagnosis, higher cumulative anthracycline dose, and radiation to the thorax. High-dose cyclophosphamide and ifosfamide were not associated with a reduction of LVSF. Vincristine sulfate was associated with a nonsignificant decrease of cardiac function (P = .07). Epirubicin hydrochloride was as cardiotoxic as doxorubicin when corrected for tumor efficacy, and daunorubicin hydrochloride seemed less cardiotoxic., Conclusions: A high percentage (27%) of young adult CCSs have an abnormal cardiac function. The strongest predictors of subclinical cardiac dysfunction are anthracycline dose, cardiac irradiation, and younger age at diagnosis. There is a suggestion that daunorubicin is less cardiotoxic than other anthracyclines.

Background: To ensure evidence-based decision making in pediatric oncology systematic reviews are necessary. The objective of our study was to evaluate the methodological quality of all currently existing systematic reviews in pediatric oncology., Methods: We identified eligible systematic reviews through a systematic search of the literature. Data on clinical and methodological characteristics of the included systematic reviews were extracted. The methodological quality of the included systematic reviews was assessed using the overview quality assessment questionnaire, a validated 10-item quality assessment tool. We compared the methodological quality of systematic reviews published in regular journals with that of Cochrane systematic reviews., Results: We included 117 systematic reviews, 99 systematic reviews published in regular journals and 18 Cochrane systematic reviews. The average methodological quality of systematic reviews was low for all ten items, but the quality of Cochrane systematic reviews was significantly higher than systematic reviews published in regular journals. On a 1-7 scale, the median overall quality score for all systematic reviews was 2 (range 1-7), with a score of 1 (range 1-7) for systematic reviews in regular journals compared to 6 (range 3-7) in Cochrane systematic reviews (p<0.001)., Conclusion: Most systematic reviews in the field of pediatric oncology seem to have serious methodological flaws leading to a high risk of bias. While Cochrane systematic reviews were of higher methodological quality than systematic reviews in regular journals, some of them also had methodological problems. Therefore, the methodology of each individual systematic review should be scrutinized before accepting its results.

Background: Growth hormone deficiency (GHD) is usually the first and most frequent endocrine problem occurring after cranial radiotherapy (CRT). The aim of this systematic review was to evaluate the existing evidence of the prevalence and risk factors of radiation-induced GHD in childhood cancer survivors., Methods: MEDLINE, EMBASE and CENTRAL were searched for studies reporting on radiation-induced GHD in childhood cancer survivors. Information about study characteristics, prevalence and risk factors was abstracted and the quality of each study was assessed. A meta-regression analysis was performed., Results: The prevalence of radiation-induced GHD was estimated in 33 studies. Most studies had methodological limitations. The prevalence varied considerably between 0% and 90.9%. Selecting only the studies with adequate peak GH cut-off limits (<5 microg/L) resulted in 3 studies. In these studies the prevalence ranged from 29.0% to 39.1%, with a pooled prevalence of 35.6%. Higher CRT dose and longer follow-up time have been suggested to be the main risk factors of GHD by studies included in this review. The meta-regression analysis showed that the wide variation in the prevalence of GHD could be explained by differences in maximal CRT dose., Conclusions: GHD is a frequent consequence after CRT in childhood cancer survivors. The prevalence of radiation-induced GHD ranged from 29.0% to 39.1% when selecting only studies with adequate peak GH cut-off limits. Higher CRT dose and longer follow-up time are the main risk factors. More well-designed studies are needed to accurately estimate the prevalence of GHD and to define the exact CRT threshold dose.

Anthracycline-induced cardiotoxicity after treatment for childhood cancer is a considerable and serious problem. In this review, important insight into the current state of the evidence on the use of different cardioprotective agents, different anthracycline analogues, and different anthracycline infusion durations to reduce or prevent cardiotoxicity in children treated with anthracyclines is provided. It has become clear that, at the present time, there is not enough reliable evidence for many aspects of the prevention of anthracycline-induced cardiotoxicity in children. More high quality research is necessary. Suggestions for future research have been presented. As the results of these new studies become available, it will hopefully be possible to develop evidence-based recommendations for preventing anthracycline-induced cardiotoxicity in children. Until then, we can only advise care providers to carefully monitor the cardiac function of children treated with anthracyclines. With regard to the use of the cardioprotectant dexrazoxane, it might be justified to use dexrazoxane in children if the risk of cardiac damage is expected to be high. However, for each individual patient, care providers should weigh the cardioprotective effect of dexrazoxane against the possible risk of adverse effects including a lower response rate. We recommend its use in the context of well-designed studies.

The use of anthracyclines is limited by a dose-dependent cardiotoxicity (A-CT). The aim of this study was to gain insight in the currently available guidelines for monitoring cardiotoxicity during anthracycline therapy in children and in the monitoring recommendations currently used in European paediatric oncology trials. An extensive literature search to identify guidelines was performed and one guideline was identified. Twelve protocols including anthracycline therapy were evaluated. With regard to the minimally required diagnostic tests, parameters and definitions of A-CT most protocols roughly followed the guideline. However, both monitoring schedules and recommendations to prevent further cardiac damage in case A-CT was diagnosed varied widely between protocols and only a minority of the protocols followed the recommendations of the guideline. In conclusion, despite an existing guideline, there is a wide variation in the recommendations for monitoring cardiac function during anthracycline therapy in the currently used European paediatric oncology protocols. A possible explanation could be the lack of rigorous evidence on the most optimal way to monitor cardiac function in children treated with anthracyclines. There is a strong need for evidence from clinical research which can support recommendations for monitoring cardiac function during anthracycline therapy for childhood cancer. In the meantime, it is important to standardize the used cardiac monitoring schedules.

The cumulative incidence of anthracycline-induced clinical heart failure (A-CHF) in a large cohort of 830 children treated with a mean cumulative anthracycline dose of 288 mg/m2 (median 280 mg/m2; range 15-900 mg/m2) with a very long and complete follow-up after the start of anthracycline therapy (mean 8.5 years; median 7.1 years; range 0.01-28.4 years) was 2.5%. A cumulative anthracycline dose of 300 mg/m2 or more was the only independent risk factor (relative risk (RR)=8). The estimated risk of A-CHF increased with time to 5.5% at 20 years after the start of anthracycline therapy; 9.8% if treated with 300 mg/m2 or more. In conclusion, 1 in every 10 children treated with a cumulative anthracycline dose of 300 mg/m2 or more will eventually develop A-CHF. This is an extremely high risk and it reinforces the need of re-evaluating the cumulative anthracycline dose used in different treatment protocols and to define strategies to prevent A-CHF which could be implemented in treatment protocols.

The cumulative incidence of peripartum anthracycline-induced clinical heart failure (A-CHF) was evaluated in a cohort of 53 childhood cancer survivors who had delivered one or more children. None of them developed peripartum A-CHF (cumulative incidence 0%; 95% confidence interval (CI) 0-5.7%). The mean follow-up time after the first administration of anthracycline therapy was 20.3 years. They received a mean cumulative anthracycline dose of 267 mg/m2. It is worth noticing that even 2 patients with A-CHF before pregnancy did not develop peripartum A-CHF. Since there were no cases of peripartum A-CHF in our cohort, it was not possible to evaluate associated risk factors. In conclusion, this study demonstrates a low risk of developing peripartum A-CHF in childhood cancer survivors. However, more cohort studies with adequate power and long-term follow-up are needed to reliably evaluate the cumulative incidence of peripartum anthracycline-induced cardiotoxicity (both clinical and asymptomatic) and associated risk factors.

Purpose: To evaluate the existing evidence regarding the long-term risk of cardiovascular disease (CVD) after radiotherapy for childhood cancer., Patients and Methods: MEDLINE and EMBASE were searched for articles reporting on radiation-induced CVD after childhood cancer published between 1966 and October 2002. Information about study design, population, treatment, outcome and risk factors were abstracted and the quality of each study was assessed., Results: Fourteen articles met all the eligibility criteria. Ten studies evaluated clinical cardiovascular events (CVE) and 11 cardiovascular mortality (CVM) after cardiac irradiation for childhood cancer. Four studies, all in survivors of Hodgkin's disease, showed a significantly increased standardised mortality ratio; a 22- to 68-fold increase compared to the general population. No study compared the risk of CVE with the general population. Three studies examined the risk of CVD (both CVM and CVE) after radiotherapy compared to an unexposed control group, and two showed a significantly increased relative risk. Many studies had important methodological limitations, related to completeness of follow-up, adjustment for other risk factors and outcome assessment in CVE studies., Conclusions: This systematic review demonstrates that the risk of CVM after cardiac irradiation for childhood cancer is increased compared to the general population and to unexposed patients. The risk of developing clinical CVE and the precise risk factors for developing CVE or CVM after radiotherapy remain unclear. New well-designed studies are needed to reliably evaluate the long-term risk of CVD following radiotherapy and associated risk factors.