Risk Prediction Models for Myocardial Dysfunction and Heart Failure in Patients with Current or Prior Cancer.

PURPOSE OF REVIEW: Cancer patients are at risk for treatment-related myocardial dysfunction and heart failure during or after treatment. Risk prediction models have the potential to play an important role in identifying patients at high or low risk in order to take appropriate measures. Here, we review their current role. RECENT FINDINGS: More and more risk prediction models are currently being developed. Unfortunately, they vary widely in their ability to identify patients and survivors at risk for myocardial dysfunction or heart failure, from very poor to strong. Part of this variation might be explained by methodological limitations of the models, but due to a lack of reporting it is not possible to completely assess this. There lies great potential in the improvement of the quality and the use of risk prediction models to inform patients and clinicians on the absolute risk of cardiac events in order to guide care.

Rapid COJEC Induction Therapy for High-risk Neuroblastoma Patients - Cochrane Review.

BACKGROUND: Neuroblastoma is a rare malignant disease and patients with high-risk neuroblastoma have a poor prognosis. Rapid COJEC induction chemotherapy means (almost) the same total doses given within a shorter time period. In theory, rapid COJEC could reduce the risk of drug resistance and it has been considered as a potential candidate for improving the outcome. METHODS: The objective was to evaluate effects of rapid COJEC compared to standard induction chemotherapy in patients with high-risk neuroblastoma. We searched the databases CENTRAL, MEDLINE, and EMBASE from inception to 11 November 2014 and included randomized controlled trials. RESULTS: We identified one relevant randomized controlled trial with 130 participants receiving rapid COJEC and 132 participants receiving standard OPEC/COJEC induction chemotherapy. There was no statistically significant difference between the treatment groups in complete response (risk ratio 0.99, 95% confidence interval 0.71 to 1.38, P=0.94) and treatment-related mortality (risk ratio 1.21, 95% confidence interval 0.33 to 4.39, P=0.77). A statistically significant difference in favor of the standard treatment arm was identified for the following early toxicities: febrile neutropenia, septicemia, and renal toxicity. CONCLUSION: The differences in complete response and treatment-related mortality between treatment alternatives were not statistically significantly different. Based on the currently available evidence, we are uncertain about the effects of rapid COJEC induction chemotherapy in patients with high-risk neuroblastoma.

Retinoic Acid for High-risk Neuroblastoma Patients after Autologous Stem Cell Transplantation - Cochrane Review.

BACKGROUND: Neuroblastoma is a rare malignant disease and patients with high-risk neuroblastoma have a poor prognosis. Retinoic acid has been shown to inhibit growth of human neuroblastoma cells and has been considered as a potential candidate for improving the outcome. METHODS: The objective was to evaluate effects of retinoic acid after consolidation with high-dose chemotherapy and bone marrow transplantation as compared to placebo or no further treatment in patients with high-risk neuroblastoma. We searched the databases CENTRAL, MEDLINE, and EMBASE from inception to 01 October 2014 and included randomized controlled trials. RESULTS: We identified one relevant randomized controlled trial with 50 participants receiving retinoic acid and 48 participants receiving no further therapy. There was no statistically significant difference between the treatment groups in overall survival (hazard ratio 0.87, 95% confidence interval 0.46-1.63, P=0.66) and event-free survival (hazard ratio 0.86, 95% confidence interval 0.50-1.49, P=0.59). We did not identify results for other outcomes, including toxicity. CONCLUSION: The difference in overall and event-free survival between treatment alternatives was not statistically significantly different. Based on the currently available evidence, we are uncertain about the effects of retinoic acid after bone marrow transplantation in patients with high-risk neuroblastoma.

The EKZ/AMC childhood cancer survivor cohort: methodology, clinical characteristics, and data availability.

PURPOSE: Childhood cancer survivors are at high risk of late adverse effects of cancer treatment, but there are still many gaps in evidence about these late effects. We described the methodology, clinical characteristics, data availability, and outcomes of our cohort study of childhood cancer survivors. METHODS: The Emma Children's Hospital/Academic Medical Center (EKZ/AMC) childhood cancer survivor cohort is an ongoing single-center cohort study of ≥5-year childhood cancer survivors, which started in 1996 simultaneously with regular structured medical outcome assessments at our outpatient clinic. RESULTS: From 1966 to 2003, 3,183 eligible children received primary cancer treatment in the EKZ/AMC, of which 1,822 (57.2 %) survived ≥5 years since diagnosis. Follow-up time ranged from 5.0 to 42.5 years (median, 17.7). Baseline primary cancer treatment characteristics were complete for 1,781 (97.7 %) survivors, and 1,452 (79.7 %) survivors visited our outpatient clinic. Baseline characteristics of survivors who visited the clinic did not differ from those without follow-up. Within our cohort, 54 studies have been conducted studying a wide range of late treatment-related effects. CONCLUSIONS: The EKZ/AMC childhood cancer survivor cohort provides a strong structure for ongoing research on the late effects of childhood cancer treatment and will continuously contribute in reducing evidence gaps concerning risks and risk groups within this vulnerable population. IMPLICATIONS FOR CANCER SURVIVORS: Our large cohort study of childhood cancer survivors with complete baseline characteristics and unique, long-term medical follow-up decreases gaps in evidence about specific risks of late effects and high-risk groups, with the ultimate goal of improving the quality of care for childhood cancer survivors.

The volume effect in paediatric oncology: a systematic review.

BACKGROUND: For several adult cancer types, there is evidence that treatment in high volume hospitals, high case volume providers, or in specialised hospitals leads to a better outcome. The aim of this study is to give an overview of the existing evidence regarding the volume effect in paediatric oncology related to the quality of care or survival. MATERIALS AND METHODS: An extensive search was carried out for studies on the effect of provider case volume on the quality of care or survival in childhood cancer. Information about study characteristics, comparisons, results, and quality assessment were abstracted. RESULTS: In total, 14 studies were included in this systematic review. Studies with a low risk of bias provide evidence that treatment of children with brain tumours, acute lymphoblastic leukaemia, osteosarcoma, Ewing's sarcoma, or children receiving treatment with allogenic bone marrow transplantation in higher volume hospitals, specialised hospitals, or by high case volume providers, is related with a better outcome. CONCLUSIONS: This systematic review provides support for the statement that higher volume hospitals, higher case volume providers, and specialised hospitals are related to the better outcome in paediatric oncology. No studies reported a negative effect of a higher volume.

Validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline-induced cardiotoxicity in children.

BACKGROUND: The use of anthracyclines as effective antineoplastic drugs is limited by the occurrence of cardiotoxicity. Multiple genetic variants predictive of anthracycline-induced cardiotoxicity (ACT) in children were recently identified. The current study was aimed to assess replication of these findings in an independent cohort of children. PROCEDURE: . Twenty-three variants were tested for association with ACT in an independent cohort of 218 patients. Predictive models including genetic and clinical risk factors were constructed in the original cohort and assessed in the current replication cohort. RESULTS: . We confirmed the association of rs17863783 in UGT1A6 and ACT in the replication cohort (P = 0.0062, odds ratio (OR) 7.98). Additional evidence for association of rs7853758 (P = 0.058, OR 0.46) and rs885004 (P = 0.058, OR 0.42) in SLC28A3 was found (combined P = 1.6 × 10(-5) and P = 3.0 × 10(-5), respectively). A previously constructed prediction model did not significantly improve risk prediction in the replication cohort over clinical factors alone. However, an improved prediction model constructed using replicated genetic variants as well as clinical factors discriminated significantly better between cases and controls than clinical factors alone in both original (AUC 0.77 vs. 0.68, P = 0.0031) and replication cohort (AUC 0.77 vs. 0.69, P = 0.060). CONCLUSIONS: . We validated genetic variants in two genes predictive of ACT in an independent cohort. A prediction model combining replicated genetic variants as well as clinical risk factors might be able to identify high- and low-risk patients who could benefit from alternative treatment options.

The Dutch Childhood Oncology Group guideline for follow-up of asymptomatic cardiac dysfunction in childhood cancer survivors.

BACKGROUND: The Late Effects of Childhood Cancer task force of the Dutch Childhood Oncology Group (DCOG LATER) developed a guideline for follow-up of asymptomatic cardiac dysfunction in childhood cancer survivors (CCS). In this paper, we present the methods, available evidence and final recommendations of our guideline. MATERIALS AND METHODS: A multidisciplinary working group specified clinical questions that should be answered to get to recommendations for the guideline. We carried out short or extensive evidence summaries and determined methodological quality of studies and levels of evidence in order to answer all clinical questions. When evidence was lacking for CCS, we carefully extrapolated evidence from other populations. Final recommendations were based on evidence and consensus. RESULTS: There was high-level evidence for the increased risk of cardiac dysfunction in CCS and its main risk factors. Evidence was lacking regarding the prognosis, diagnosis and treatment of cardiac dysfunction in CCS. We recommended echocardiographic screening for asymptomatic cardiac dysfunction in CCS treated with cardiotoxic treatments and counseling about potential advantages and disadvantages of our screening recommendations. CONCLUSION: The DCOG LATER guideline recommends risk-based screening for asymptomatic cardiac dysfunction in CCS, but it should be noted that recommendations are not completely supported by evidence in CCS.

The use of liposomal anthracycline analogues for childhood malignancies: A systematic review.

In an effort to prevent or reduce anthracycline-induced cardiotoxicity, liposomal anthracyclines have been developed. The objective of this systematic review was to summarise all available evidence on the benefits and risks of liposomal anthracyclines in children with cancer. We searched databases (MEDLINE (1966-September 2009), EMBASE (1980-September 2009) and CENTRAL (The Cochrane Library, issue 3 2009)), reference lists of relevant articles and ongoing trial databases for relevant studies. Two reviewers independently performed study selection, data extraction and quality assessment of included studies. No randomised controlled trials (RCTs) or controlled clinical trials (CCTs) were found. Fifteen observational studies described the use of liposomal anthracyclines in children with cancer. Most patients had been treated extensively in the past. Some patients developed cardiotoxicity, serious allergic reactions, mucositis, infections, hematotoxicities and/or hepatotoxicity after single agent treatment. However, due to the low quality of the currently available research, it is unclear what the exact risks are. In conclusion, there is no evidence available from RCTs or CCTs about the benefits and risks of liposomal anthracyclines in children with cancer. Limited data from observational studies suggest that children treated with liposomal anthracyclines are at risk for developing cardiotoxicity and other serious toxicities. There is an urgent need for results of well-designed studies which accurately evaluate the benefits and risks of liposomal anthracyclines in children with cancer. Until high quality evidence is available, we recommend monitoring of cardiac function in childhood cancer patients treated with a liposomal anthracycline and awareness of other serious toxicities.

Pediatric oncologists and evidence-based medicine: a postal survey in The Netherlands.

BACKGROUND: The interest in evidence-based medicine (EBM) is still increasing throughout medicine, but the precise role of EBM in the field of pediatric oncology remains unclear. We undertook this survey to evaluate the attitude of Dutch pediatric oncologists and pediatric oncologists in training towards EBM and their views on how to move from opinion-based medicine to EBM. PROCEDURE: A questionnaire was sent to all pediatric oncologists (n = 44) and pediatric oncologists in training (n = 13) of the 8 university medical centers in the Netherlands. RESULTS: The questionnaire was returned by 71% of the pediatric oncologists and pediatric oncologists in training. The majority had a positive attitude towards EBM, but at the moment only approximately 50% of their clinical practice was thought to be evidence-based. The most important barrier to practicing EBM in pediatric oncology was a lack of time. However, only a minority of the respondents thought that more time was an appropriate method to facilitate the use of EBM in pediatric oncology. The majority of pediatric oncologists and pediatric oncologists in training would prefer to be able to use EBM summaries, guidelines and protocols. CONCLUSIONS: Despite the positive attitude of the majority of pediatric oncologists and pediatric oncologists in training towards EBM, only half of clinical practice is currently believed to be evidence-based. By using EBM summaries, guidelines and protocols as time-saving methods the use of EBM in pediatric oncology practice may be improved.

Cardioprotective interventions for cancer patients receiving anthracyclines.

BACKGROUND: Anthracyclines are among the most effective chemotherapeutic agents in the treatment of numerous malignancies. Unfortunately, their use is limited by a dose-dependent cardiotoxicity. In an effort to prevent this cardiotoxicity, different cardioprotective agents have been studied. OBJECTIVES: The objective of this review was to assess the efficacy of different cardioprotective agents in preventing heart damage in cancer patients treated with anthracyclines. SEARCH STRATEGY: We searched the databases of the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 2, 2007), MEDLINE (1966 to April 2007) and EMBASE (1980 to April 2007). In addition, we handsearched reference lists and conference proceedings of the SIOP and ASCO meetings (1998 to 2006). SELECTION CRITERIA: Randomised controlled trials (RCTs) in which any cardioprotective agent was compared to no additional or placebo therapy in cancer patients (children and adults) receiving anthracyclines. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection, quality assessment and data-extraction including adverse effects. MAIN RESULTS: We identified RCTs for seven cardioprotective agents: N-acetylcysteine, phenetylamines, coenzyme Q10, combination of vitamins E and C and N-acetylcysteine, L-carnitine, carvedilol and dexrazoxane (mostly adults with advanced breast cancer). All studies had methodological limitations. For the first six agents, there were too few studies to allow pooling of results. None of the individual studies showed a cardioprotective effect. The nine included studies of dexrazoxane enrolled 1403 patients. The meta-analysis of dexrazoxane showed a statistically significant benefit in favour of dexrazoxane for the occurrence of heart failure (Relative Risk (RR) 0.29, 95% CI 0.20 to 0.41). No evidence was found for a difference in response rate or survival between the dexrazoxane and control group. Only for one adverse effect (abnormal white blood cell count at nadir) a difference in favour of the control group was identified. AUTHORS' CONCLUSIONS: For cardioprotective agents for which pooling was impossible, no definitive conclusions can be made about their efficacy. Dexrazoxane prevents heart damage and no evidence for a difference in response rate or survival between the dexrazoxane and control group was identified. Only for an abnormal white blood cell count at nadir a clearly significant difference in favour of the control group was identified. We conclude that if the risk of cardiac damage is expected to be high, it might be justified to use dexrazoxane in patients with cancer treated with anthracyclines. However, for each individual patient clinicians should weigh the cardioprotective effect of dexrazoxane against the possible risk of adverse effects.

Different anthracycline derivates for reducing cardiotoxicity in cancer patients.

BACKGROUND: The use of anthracycline chemotherapy is limited by the occurrence of cardiotoxicity. In an effort to prevent this cardiotoxicity, different anthracycline derivates have been studied. OBJECTIVES: The primary objective was to determine the occurrence of cardiotoxicity with the use of different anthracycline derivates in cancer patients. SEARCH STRATEGY: We searched the databases of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1, 2005), MEDLINE (1966 to April 2005) and EMBASE (1980 to April 2005). In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trials databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) in which different anthracycline derivates were compared in cancer patients (children and adults). DATA COLLECTION AND ANALYSIS: Two authors independently performed the study selection, quality assessment and data-extraction including adverse effects. MAIN RESULTS: We identified five RCTs of varying quality addressing epirubicin versus doxorubicin (1036 patients) with the same dose. The meta-analysis showed no evidence for a significant difference in the occurrence of clinical heart failure between the treatment groups (RR = 0.36, 95% CI 0.12 to 1.11). However, there is some suggestion of a lower rate of clinical heart failure in patients treated with epirubicin. We identified two RCTs with varying quality addressing liposomal-encapsulated doxorubicin versus conventional doxorubicin (521 patients). The meta-analysis showed a significantly lower rate of both clinical heart failure and clinical and subclinical heart failure combined in patients treated with liposomal-encapsulated doxorubicin (RR = 0.20, 95% CI 0.05 to 0.75 and RR = 0.38, 95% CI 0.24 to 0.59 respectively). It should be noted that in one of the studies patients in the liposomal-encapsulated doxorubicin group received a higher cumulative anthracycline dose than patients in the doxorubicin group. For the other possible combinations of different anthracycline derivates only one RCT was identified. AUTHORS' CONCLUSIONS: We are not able to favour either epirubicin or doxorubicin when given with the same dose. Based on the currently available evidence on heart failure, we conclude that in adults with a solid tumour liposomal-encapsulated doxorubicin should be favoured over doxorubicin. For both epirubicin versus doxorubicin and liposomal-encapsulated doxorubicin versus conventional doxorubicin no conclusions can be made about the effects of treatment in children treated with anthracyclines and also not in patients diagnosed with leukaemia. More research is needed. For other combinations of anthracycline derivates not enough evidence was available to make definitive conclusions about the occurrence of cardiotoxicity in patients treated with anthracyclines.

Different dosage schedules for reducing cardiotoxicity in cancer patients receiving anthracycline chemotherapy.

BACKGROUND: The use of anthracycline chemotherapy is limited by the occurrence of cardiotoxicity. In an effort to prevent this cardiotoxicity, different anthracycline dosage schedules (i.e. peak doses and infusion durations) have been studied. OBJECTIVES: The primary objective was to determine the occurrence of cardiotoxicity with the use of different anthracycline dosage schedules in cancer patients. SEARCH STRATEGY: We searched the databases of The Cochrane Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 2, 2004), MEDLINE (1966 to June 2004) and EMBASE (1980 to June 2004). In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trials databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) in which different anthracycline dosage schedules were compared in cancer patients (children and adults). DATA COLLECTION AND ANALYSIS: Two authors independently performed the study selection, quality assessment and data-extraction including adverse effects. MAIN RESULTS: We identified six RCTs of varying quality addressing different anthracycline infusion durations (625 patients). The meta-analysis showed a statistically significant lower rate of clinical heart failure with an infusion duration of 6 hours or longer as compared to a shorter infusion duration, i.e. maximal duration of 1 hour (RR = 0.27; 95% confidence interval (CI) 0.09 to 0.81; 5 studies; 557 patients). In individual studies the infusion duration of 6 hours or longer also seemed to reduce the risk of subclinical cardiac damage. No statistically significant difference in response rate was found (RR = 0.83; 95% CI 0.45 to 1.54; 2 studies; 292 patients). No statistically significant difference in overall survival was found (HR = 1,42; 95% CI 0.61 to 3.30; 2 studies; 322 patients), but there was unexplained heterogeneity (I(2)=75%). No conclusions can be made regarding adverse effects. It should be emphasised that the majority of patients included in these studies were adults with different solid tumours. Children with leukaemia could not be included in the performed meta-analyses, but they were included in the descriptive results of non-pooled studies. No RCTs addressing different anthracycline peak doses with the same cumulative anthracycline dose in both treatment groups were identified. AUTHORS' CONCLUSIONS: An anthracycline infusion duration of six hours or longer reduces the risk of clinical heart failure, and it seems to reduce the risk of subclinical cardiac damage. There is no evidence which suggests a difference in response rate and survival between both treatment groups. Since there is only a small amount of data for children and also because data obtained in adults cannot be extrapolated to children, different anthracycline infusion durations should be evaluated further in children. For different anthracycline peak doses no high quality evidence was available and therefore, no definitive conclusions can be made about the occurrence of cardiotoxicity in patients treated with different anthracycline peak doses.

Cardioprotective interventions for cancer patients receiving anthracyclines.

BACKGROUND: Anthracyclines are among the most effective chemotherapeutic agents in the treatment of numerous malignancies. Unfortunately, their use is limited by a dose-dependent cardiotoxicity. In an effort to prevent this cardiotoxicity, different cardioprotective agents have been studied. OBJECTIVES: The objective of this review was to assess the efficacy of different cardioprotective agents in preventing heart damage in cancer patients treated with anthracyclines. SEARCH STRATEGY: We searched the databases of CENTRAL (The Cochrane Library, Issue 3, 2002), MEDLINE (1966 to August 2002) and EMBASE (1980 to August 2002). In addition, we handsearched reference lists and conference proceedings of the International Society for Paediatric Oncology (SIOP) and the American Society of Clinical Oncology (ASCO) (1998 to 2002). SELECTION CRITERIA: Randomised controlled trials (RCTs) in which any cardioprotective agent was compared to no additional or placebo therapy in cancer patients (children and adults) receiving anthracyclines. DATA COLLECTION AND ANALYSIS: Two reviewers independently performed the study selection, quality assessment and data-extraction including adverse effects. MAIN RESULTS: We identified RCTs for 5 cardioprotective agents: N-acetylcysteine (1 study; 54 patients), phenetylamines (2 studies; 100 patients), coenzyme Q10 (1 study; 20 patients), combination of vitamin E, vitamin C and N-acetylcysteine (1 study; 14 patients) and dexrazoxane (6 studies; 1013 patients). All studies had methodological limitations. Due to the insufficient number of studies, for the first four mentioned cardioprotective agents pooling of the results was impossible. None of the individual studies showed a cardioprotective effect. The meta-analysis of the dexrazoxane-studies showed a statistically significant benefit in favour of dexrazoxane for the occurrence of heart failure (Relative Risk (RR) = 0.28, 95% Confidence Interval (CI) 0.18 to 0.42, P < 0.00001). No statistically significant difference in response rate between the dexrazoxane and control group was found (RR = 0.88, 95% CI 0.77 to 1.01, P = 0.06), but there was some suggestion that patients treated with dexrazoxane might have a lower anti-tumour response rate. Our meta-analysis of survival showed no significant difference between the dexrazoxane and control group. For adverse effects pooling was impossible. However, no important differences in the occurrence of side effects were found. The majority of the patients included in this meta-analysis were adults with advanced breast cancer. AUTHORS' CONCLUSIONS: For cardioprotective agents for which pooling was impossible no high quality evidence was available and therefore, no definitive conclusions can be made about their efficacy. Dexrazoxane prevents heart damage, however there was some suggestion that patients treated with dexrazoxane might have a lower anti-tumour response rate. There was no significant difference in survival between the dexrazoxane and control group. We conclude that if the risk of cardiac damage is expected to be high, it might be justified to use dexrazoxane in patients with cancer treated with anthracyclines. However, for each individual patient clinicians should weigh the cardioprotective effect of dexrazoxane against the possible risk of a lower response rate.

Cumulative incidence and risk factors of mitoxantrone-induced cardiotoxicity in children: a systematic review.

Mitoxantrone is believed to maintain anthracycline antitumour activity but be associated with a reduced cardiotoxicity. The aim of this study was to evaluate the evidence for the cumulative incidence of and risk factors for mitoxantrone-induced cardiotoxicity (M-CT) in children treated for childhood cancers. After an extensive literature search, 17 studies were included. The cumulative incidence varied between 0 and 6.7% in the 16 studies evaluating symptomatic M-CT and between 0 and 80% in the 11 studies evaluating asymptomatic M-CT. Risk factors for developing M-CT remain unclear. All studies had serious methodological limitations. In conclusion, children treated with mitoxantrone are at risk of developing M-CT, but due to the low quality of the current evidence, the exact cumulative incidence and risk factors for M-CT remain unclear. It is too early to conclude that in children mitoxantrone is less cardiotoxic than anthracyclines. More well-designed studies are needed to reliably evaluate the incidence of M-CT and its associated risk factors.

Frequency and risk factors of subclinical cardiotoxicity after anthracycline therapy in children: a systematic review.

BACKGROUND: The aim of this systematic review was to summarise and appraise the published evidence with regard to the frequency and risk factors of subclinical cardiotoxicity in apparently healthy survivors of childhood cancer after anthracycline therapy. PATIENTS AND METHODS: A search was made in Medline for studies published between 1966 and May 2001 that included >50 children and reported on the frequency of measures of subclinical cardiotoxicity. Information about the studies was abstracted by two reviewers and a validity score was calculated for each study. RESULTS: The reported frequency of subclinical cardiotoxicity varied between 0% and 57% in the 25 studies included. Differences in outcome definitions of subclinical cardiotoxicity and differences in study patients with respect to the dose of anthracycline seemed to explain part of the wide variance of the frequency of subclinical cardiotoxicity. Fourteen of the 25 studies showed serious methodological limitations. CONCLUSIONS: The reported frequency of subclinical cardiotoxicity shows a wide variation. Well designed studies with accurate and precise outcome measurements in well described groups of patients, after a sufficiently long follow-up period, are needed to obtain more insight into the frequency and importance of risk factors, and the clinical consequences of anthracycline-related subclinical cardiotoxicity.

Frequency and risk factors of anthracycline-induced clinical heart failure in children: a systematic review.

BACKGROUND: Anthracyclines are essential for the treatment of the children with cancer. We performed a systematic review to evaluate the existing evidence of the frequency and risk factors of anthracycline-induced clinical heart failure (A-CHF) in children. DESIGN: Medline was searched for articles reporting the frequency of A-CHF, published from 1966 to December 2000. Information about study features, risk factors and frequency were abstracted, and a validity score was given for each study. The potential predictive factors of A-CHF were analysed both within and across the studies. RESULTS: The frequency of A-CHF in children was estimated in 30 studies described in 25 articles. All studies have serious methodological limitations. The frequency varied between 0% and 16%. In the analysis across the studies the type of anthracyclines and the maximal dose in 1 week explain a considerable part of the variation of the frequency of A-CHF. CONCLUSIONS: Doxorubicin and a dose above 45 mg/m2 within 1 week seemed to increase the frequency of A-CHF. Well designed and executed studies are needed to accurately estimate the frequency of A-CHF and reliably assess the importance of potential risk factors.

Anthracycline-induced clinical heart failure in a cohort of 607 children: long-term follow-up study.

PURPOSE: To determine the early and late cumulative incidence of anthracycline-induced clinical heart failure (A-CHF) after anthracycline therapy in childhood and to identify associated risk factors. PATIENTS AND METHODS: The cumulative incidence of A-CHF and the risk factors of A-CHF were assessed in a cohort of 607 children who had been treated with anthracyclines between 1976 and 1996. For 96% of the cohort, we obtained the clinical status up to at least January 1997. The mean follow-up time was 6.3 years. RESULTS: The cumulative incidence of A-CHF was 2.8%, after a mean follow-up time of 6.3 years and a mean cumulative dose of anthracyclines of 301 mg/m(2). A cumulative dose of anthracycline higher than 300 mg/m(2) was associated with an increased risk of A-CHF (relative risk, 11.8; 95% confidence interval, 1.6 to 59.5) compared with a cumulative dose lower than 300 mg/m(2). The estimated risk of A-CHF increased with time after the start of anthracycline chemotherapy to 2% after 2 years and 5% after 15 years. CONCLUSION: Up to 5% of patients will develop A-CHF 15 years after treatment, and patients treated with a cumulative dose of anthracyclines higher than 300 mg/m(2) are at highest risk for A-CHF. This is thus a considerable and serious problem among these young patients. The findings reinforce the need for strategies for early detection of patients at risk for A-CHF and for the evaluation of other chemotherapeutic possibilities or cardioprotective agents in relation to the survival.