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.

High-dose chemotherapy followed by autologous haematopoietic cell transplantation for children, adolescents, and young adults with primary metastatic Ewing sarcoma.

BACKGROUND: Ewing sarcomas are solid tumours of the bone and soft tissue, that usually affect children, adolescents, and young adults. The incidence is about three cases per million a year, with a peak incidence at 12 years of age. Metastatic disease is detected in about 20 % to 30% of people, and is typically found in the lungs, bone, bone marrow, or a combination of these. Presence of metastatic disease at diagnosis (primary metastatic disease) is the most important adverse prognostic factor, and is associated with a five-year survival lower than 30%. High-dose chemotherapy (HDC) followed by autologous haematopoietic cell transplantation (AHCT) is used in various solid tumours with unfavourable prognoses in children, adolescents, and young adults. It has also been used as rescue after multifocal radiation of metastases. The hypothesis is that HDC regimens may overcome the resistance to standard multidrug chemotherapy and improve survival rates. OBJECTIVES: To assess the effects of high-dose chemotherapy with autologous haematopoietic cell transplantation compared with conventional chemotherapy in improving event-free survival, overall survival, quality-adjusted survival, and progression-free survival in children, adolescents, and young adults with primary metastatic Ewing sarcoma, and to determine the toxicity of the treatment. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, conference proceedings from major international cancer-related conferences, and ongoing trial registers until January 2020. We also searched reference lists of included articles and review articles. SELECTION CRITERIA: We included randomised controlled trials (RCTs) or (historical) controlled clinical trials (CCTs) comparing the effectiveness of HDC and AHCT with conventional chemotherapy for children, adolescents, and young adults (younger than 30 years at the date of diagnostic biopsy) with primary metastatic Ewing sarcoma. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified one RCT, which investigated the effects of HDC with AHCT versus conventional chemotherapy with whole lung irradiation (WLI) in people with Ewing sarcoma metastasised to the lungs only at diagnosis. Only a selection of the participants were eligible for our review (N = 267: HDC with AHCT group N = 134; control group N = 133). There may be no difference in event-free survival between the two treatment groups (hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.59 to 1.17; low-certainty evidence). We downgraded one level each because of study limitations and imprecision. Overall survival and toxicity were not reported separately for the participants eligible for this review, while quality-adjusted survival and progression-free survival were not reported at all. We did not identify any studies that addressed children, adolescents, and young adults with Ewing sarcoma with metastases to other locations. AUTHORS' CONCLUSIONS: In people with Ewing sarcoma with primary metastases to locations other than the lungs, there is currently no evidence from RCTs or CCTs to determine the efficacy of HDC with AHCT compared to conventional chemotherapy. Based on low-certainty evidence from one study (267 participants), there may be no difference in event-free survival between children, adolescents, and young adults with primary pulmonary metastatic Ewing sarcoma who receive HDC with AHCT and those who receive conventional chemotherapy with WLI. Further high-quality research is needed. Results are anticipated for the EuroEwing 2008R3 study, in which the effects of HDC with treosulfan and melphalan followed by AHCT on survival, in people with Ewing sarcoma with metastatic disease to bone, other sites, or both were explored. Achieving high-quality studies in a selection of people with rare sarcoma requires long-term, multi-centre, international participant inclusion.

High-dose chemotherapy followed by autologous haematopoietic cell transplantation for children, adolescents, and young adults with first recurrence of Ewing sarcoma.

BACKGROUND: Ewing sarcoma is a solid tumour, which is the second most common primary bone malignancy in children, often occurring in the long bones and pelvis. An incidence rate of 4.5 per million a year is reported, with a peak incidence of 11 per million at the age of 12 years. Despite more intensive chemotherapy, 30% to 40% of young people with Ewing sarcoma will have recurrence of the disease. Less than 30% of young people with a recurrence of Ewing sarcoma are alive at 24 months, and less than 10% are alive at 48 months. High-dose chemotherapy (HDC), followed by autologous haematopoietic cell transplantation (AHCT), is used in a variety of paediatric groups with diverse solid tumours. The hypothesis is that HDC regimens may overcome resistance to standard polychemotherapy, and this way may eradicate minimal residual disease, leading to improved survival after a first recurrence of disease. OBJECTIVES: To assess the efficacy of HDC with AHCT versus conventional chemotherapy in improving event-free survival, overall survival, quality-adjusted survival, and progression-free survival in children, adolescents, and young adults with first recurrence of Ewing sarcoma, and to determine the toxicity of the treatment. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, conference proceedings from the SIOP, ASPHO, CTOS, ASBMT, EBMT, and EMSOS, and two trial registries in January 2020. We also searched reference lists of relevant articles and review articles. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) or (historical) controlled clinical trials (CCTs) comparing the effectiveness of HDC plus AHCT with conventional chemotherapy for children, adolescents, and young adults (up to 30 years old at the date of diagnostic biopsy) with a first recurrence of Ewing sarcoma. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We did not identify any eligible studies. AUTHORS' CONCLUSIONS: Since we did not identify any eligible studies, we are unable to draw any conclusions about the efficacy and toxicity of HDC with AHCT versus conventional chemotherapy in children, adolescents, and young adults with a first recurrence of Ewing sarcoma. Further high-quality research is urgently needed.

Hearing loss after platinum treatment is irreversible in noncranial irradiated childhood cancer survivors.

Cisplatin and carboplatin are effective antineoplastic agents. They are also considered to be potentially highly ototoxic. To date, no long-term follow-up data from well-documented cohorts with substantial numbers of childhood cancer survivors (CCS) with platinum-related hearing loss are available. Therefore, in this study, we studied the reversibility of ototoxicity from discontinuation of treatment onwards in a national cohort of platinum-treated survivors with hearing loss at the end of cancer treatment. Of the 168 CCS with follow-up audiograms, we longitudinally evaluated the course of hearing function in 61 CCS who showed hearing impairment at discontinuation of treatment according to the Münster criteria (>20 dB at ≥4-8 kHz). Survivors were treated with platinum (median total cumulative dose cisplatin: 480 mg/m2 and median total cumulative dose carboplatin: 2520 mg/m2). Median follow-up time was 5.5 years (range: 1.0-28.8 years). The results showed that none of these survivors revealed improvement of hearing function even till 28.8 years after discontinuation of treatment (grade <2b during long-term follow-up). An increase in hearing loss with two or three Münster degrees was observed in five of 61 survivors after 1.6-19.6 years. Overall, this indicates that ototoxicity after platinum treatment may be irreversible and that longitudinal clinical audiological monitoring and care is required in long-term survivors of childhood cancer on a large scale.

Minimally invasive surgery versus open surgery for the treatment of solid abdominal and thoracic neoplasms in children.

BACKGROUND: Minimally invasive surgery (MIS) is an accepted surgical technique for the treatment of a variety of benign diseases. Presently, the use of MIS in patients with cancer is progressing. However, the role of MIS in children with solid neoplasms is less clear than it is in adults. Although the use of diagnostic MIS to obtain biopsy specimens for pathology is accepted in paediatric surgical oncology, there is limited evidence to support the use of MIS for the resection of malignancies. This review is the second update of a previously published Cochrane review. OBJECTIVES: To ascertain differences in outcome between the minimally invasive and open surgical approaches for the treatment of solid intra-abdominal or intra-thoracic neoplasms in children. The primary outcomes of interest are OS, EFS, port-site metastases and recurrence rate; the secondary outcome of interest is surgical morbidity. SEARCH METHODS: We searched CENTRAL (The Cochrane Library 2014, Issue 1), MEDLINE/PubMed (from 1966 to February 2014) and EMBASE/Ovid (from 1980 to February 2014) to identify relevant studies. In addition, we searched reference lists of relevant articles and reviews and the conference proceedings of the International Society for Paediatric Oncology and the American Society of Clinical Oncology from 2003 to 2013. On 1 May 2014 we scanned the ISRCTN Register (on www.controlled-trials.com), the National Institutes of Health register (on www.controlled-trials.com and www.clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform (on www.apps.who.int/trialsearch) for ongoing trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing MIS to open surgery for the treatment of solid intra-thoracic or intra-abdominal neoplasms in children (aged 0 to 18 years) were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors performed the study selection independently. MAIN RESULTS: The literature search retrieved 542 references. After screening the titles and abstracts we excluded 534 references which clearly did not meet the inclusion criteria. We assessed eight full text studies for eligibility and all of these studies were excluded from the review because they were not RCTs or CCTs. These excluded studies included case series, retrospective chart reviews and retrospective cohort studies. The scanning of reference lists and conference proceedings did not identify any additional studies and no (ongoing trials) were identified by the searches of trial registries. No studies that met the inclusion criteria of this review were identified AUTHORS' CONCLUSIONS: No RCTs or CCTs evaluating MIS for the treatment of solid intra-thoracic or intra-abdominal neoplasms in children could be identified. The current evidence base informing the use of MIS in children with solid abdominal and thoracic neoplasms is based on other study designs like case reports, retrospective chart reviews and cohort studies and should be interpreted with caution. Thus there is insufficient evidence to allow any definitive conclusions regarding the use of MIS in these patients. High quality RCTs comparing MIS to open surgery are required. To accomplish this, centres specialising in MIS in children should collaborate.

High-dose chemotherapy and autologous haematopoietic stem cell rescue for children with high-risk neuroblastoma.

BACKGROUND: Despite the development of new treatment options, the prognosis of high-risk neuroblastoma patients is still poor; more than half of patients experience disease recurrence. High-dose chemotherapy and haematopoietic stem cell rescue (i.e. myeloablative therapy) might improve survival. This review is an update of a previously published Cochrane review. OBJECTIVES: The primary objective was to compare the efficacy of myeloablative therapy with conventional therapy in children with high-risk neuroblastoma. Secondary objectives were to determine possible effects of these interventions on adverse events, late effects and quality of life. SEARCH METHODS: We searched the electronic databases CENTRAL (The Cochrane Library 2012, issue 6), MEDLINE/PubMed (1966 to June 2012) and EMBASE/Ovid (1980 to June 2012). In addition, we searched reference lists of relevant articles and the conference proceedings of the International Society for Paediatric Oncology (SIOP) (from 2002 to 2011), American Society for Pediatric Hematology and Oncology (ASPHO) (from 2002 to 2012), Advances in Neuroblastoma Research (ANR) (from 2002 to 2012) and American Society for Clinical Oncology (ASCO) (from 2008 to 2012). We searched for ongoing trials by scanning the ISRCTN register and the National Institute of Health Register (http://www.controlled-trials.com; both screened July 2012). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the efficacy of myeloablative therapy with conventional therapy in high-risk neuroblastoma patients. DATA COLLECTION AND ANALYSIS: Two authors independently performed study selection, data extraction and risk of bias assessment. If appropriate, we pooled studies. The risk ratio (RR) and 95% confidence interval (CI) was calculated for dichotomous outcomes. For the assessment of survival data, we calculated the hazard ratio (HR) and 95% CI. We used Parmar's method if hazard ratios were not reported in the study. We used a random-effects model. MAIN RESULTS: We identified three RCTs including 739 children. They all used an age of one year as the cut-off point for pre-treatment risk stratification. The updated search identified a manuscript reporting additional follow-up data for one of these RCTs. There was a statistically significant difference in event-free survival in favour of myeloablative therapy over conventional chemotherapy or no further treatment (3 studies, 739 patients; HR 0.78, 95% CI 0.67 to 0.90). There was a statistically significant difference in overall survival in favour of myeloablative therapy over conventional chemotherapy or no further treatment (2 studies, 360 patients; HR 0.74, 95% CI 0.57 to 0.98). However, when additional follow-up data were included in the analyses the difference in event-free survival remained statistically significant (3 studies. 739 patients; HR 0.79, 95% CI 0.70 to 0.90), but the difference in overall survival was no longer statistically significant (2 studies, 360 patients; HR 0.86, 95% CI 0.73 to 1.01). The meta-analysis of secondary malignant disease and treatment-related death did not show any statistically significant differences between the treatment groups. Data from one study (379 patients) showed a significantly higher incidence of renal effects, interstitial pneumonitis and veno-occlusive disease in the myeloablative group compared to conventional chemotherapy, whereas for serious infections and sepsis no significant difference between the treatment groups was identified. No information on quality of life was reported. In the individual studies we evaluated different subgroups, but the results were not univocal in all studies. All studies had some methodological limitations. AUTHORS' CONCLUSIONS: Based on the currently available evidence, myeloablative therapy seems to work in terms of event-free survival. For overall survival there is currently no evidence of effect when additional follow-up data are included. No definitive conclusions can be made regarding adverse effects and quality of life, although possible higher levels of adverse effects should be kept in mind. A definitive conclusion regarding the effect of myeloablative therapy in different subgroups is not possible. This systematic review only allows a conclusion on the concept of myeloablative therapy; no conclusions can be made regarding the best treatment strategy. Future trials on the use of myeloablative therapy for high-risk neuroblastoma should focus on identifying the most optimal induction and/or myeloablative regimen. The best study design to answer these questions is a RCT. These RCTs should be performed in homogeneous study populations (e.g. stage of disease and patient age) and have a long-term follow-up. Different risk groups, using the most recent definitions, should be taken into account.It should be kept in mind that recently the age cut-off for high risk disease was changed from one year to 18 months. As a result it is possible that patients with what is now classified as intermediate-risk disease have been included in the high-risk groups. Consequently the relevance of the results of these studies to the current practice can be questioned. Survival rates may be overestimated due to the inclusion of patients with intermediate-risk disease.

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 Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 10), MEDLINE (1966 to November 2010) and EMBASE (1980 to November 2010) databases. In addition, we handsearched reference lists, conference proceedings of the International Society of Paediatric Oncology (SIOP) and American Society of Clinical Oncology (ASCO) meetings (1998 to 2010) and ongoing trials registers. SELECTION CRITERIA: Randomised controlled trials (RCTs) in which any cardioprotective agent was compared to no additional therapy or placebo in cancer patients (children and adults) receiving anthracyclines. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection, risk of bias assessment and data extraction including adverse effects. MAIN RESULTS: We identified RCTs for the eight cardioprotective agents N-acetylcysteine, phenethylamines, coenzyme Q10, a combination of vitamins E and C and N-acetylcysteine, L-carnitine, carvedilol, amifostine and dexrazoxane (mostly for adults with advanced breast cancer). All studies had methodological limitations and for the first seven agents there were too few studies to allow pooling of results. None of the individual studies showed a cardioprotective effect. The 10 included studies on dexrazoxane enrolled 1619 patients. The meta-analysis for dexrazoxane showed a statistically significant benefit in favour of dexrazoxane for the occurrence of heart failure (risk ratio (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 groups. The results for adverse effects were ambiguous. No significant difference in the occurrence of secondary malignancies was identified. AUTHORS' CONCLUSIONS: No definitive conclusions can be made about the efficacy of cardioprotective agents for which pooling of results was impossible. Dexrazoxane prevents heart damage and no evidence for a difference in response rate or survival between the dexrazoxane and control groups was identified. The evidence available did not allow us to reach any definite conclusions about adverse effects. 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, clinicians should weigh the cardioprotective effect of dexrazoxane against the possible risk of adverse effects for each individual patient.

Treatment including anthracyclines versus treatment not including anthracyclines for childhood cancer.

BACKGROUND: One of the most important adverse effects of anthracyclines is cardiotoxicity. A well-informed decision on the use of anthracyclines in the treatment of childhood cancers should be based on evidence regarding both antitumour efficacy and cardiotoxicity. OBJECTIVES: To compare antitumour efficacy of treatment including or not including anthracyclines in children with childhood cancer. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 2), MEDLINE (1966 to March 2010) and EMBASE (1980 to March 2010). In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trials databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing treatment of any type of childhood cancer with and without anthracyclines and reporting outcomes concerning antitumour efficacy. DATA COLLECTION AND ANALYSIS: Two reviewers independently performed the study selection, risk of bias assessment and data extraction. MAIN RESULTS: We identified RCTs for six types of tumour: acute lymphoblastic leukaemia (ALL) (three trials; 912 children), Wilms' tumour (one trial; 316 children), rhabdomyosarcoma/undifferentiated sarcoma (one trial; 413 children), Ewing's sarcoma (one trial; 94 children), non-Hodgkin lymphoma (one trial; 284 children) and hepatoblastoma (one trial; 255 children). All studies had methodological limitations. For ALL no evidence of a significant difference in antitumour efficacy was identified in the meta-analyses, but in most individual studies there was a suggestion of better antitumour efficacy in patients treated with anthracyclines. For both Wilms' tumour and Ewing's sarcoma a significant difference in event-free and overall survival in favour of treatment with anthracyclines was identified, although for Wilms' tumour the significant difference in overall survival disappears with long-term follow-up. For rhabdomyosarcoma/undifferentiated sarcoma, non-Hodgkin lymphoma and hepatoblastoma no difference in antitumour efficacy between the treatment groups was identified. Clinical cardiotoxicity was evaluated in three RCTs: no significant difference between both treatment groups was identified, but in all individual studies there was a suggestion of a lower rate of clinical cardiotoxicity in patients who did not receive anthracyclines. None of the studies evaluated asymptomatic cardiac dysfunction. For other childhood cancers no RCTs were identified. AUTHORS' CONCLUSIONS: At the moment no evidence from RCTs is available which underscores the use of anthracyclines in ALL. However, "no evidence of effect", as identified in this review, is not the same as "evidence of no effect". For Wilms' tumour, rhabdomyosarcoma/undifferentiated sarcoma, Ewing's sarcoma, non-Hodgkin lymphoma and hepatoblastoma only one RCT was available and, therefore, no definitive conclusions can be made about the antitumour efficacy of treatment with or without anthracyclines in these tumours. For other childhood cancers no RCTs were identified and therefore, no conclusions can be made about the antitumour efficacy of treatment with or without anthracyclines in these tumours.

Medical interventions for treating anthracycline-induced symptomatic and asymptomatic cardiotoxicity during and after treatment for childhood cancer.

BACKGROUND: Anthracyclines are frequently used chemotherapeutic agents for childhood cancer that can cause cardiotoxicity during and after treatment. Although several medical interventions in adults with symptomatic or asymptomatic cardiac dysfunction due to other causes are beneficial, it is not known if the same treatments are effective for childhood cancer patients and survivors with anthracycline-induced cardiotoxicity. OBJECTIVES: To compare the effect of medical interventions on anthracycline-induced cardiotoxicity in childhood cancer patients or survivors with the effect of placebo, other medical interventions or no treatment. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2011, issue 1), MEDLINE/PubMed (1949 to May 2011) and EMBASE/Ovid (1980 to May 2011) for potentially relevant articles. We additionally searched reference lists of relevant articles, conference proceedings and ongoing trial databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing the effectiveness of medical interventions to treat anthracycline-induced cardiotoxicity with either placebo, other medical interventions or no treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection. One review author performed the data extraction and 'Risk of bias' assessments which were checked by another review author. MAIN RESULTS: We identified two RCTs. One trial (135 patients) compared enalapril with placebo in childhood cancer survivors with asymptomatic anthracycline induced cardiac dysfunction. The other trial (68 patients) compared a two-week treatment of phosphocreatine with a control treatment (vitamin C, ATP, vitamin E, oral coenzyme Q10) in leukaemia patients with anthracycline-induced cardiotoxicity. Both studies had methodological limitations.The RCT on enalapril showed no (statistically) significant differences in overall survival, mortality due to heart failure, development of clinical heart failure and quality of life between treatment and control group. A post-hoc analysis showed a decrease (i.e. improvement) in one measure of cardiac function (left ventricular end systolic wall stress (LVESWS): -8.62% change) compared with placebo (+1.66% change) in the first year of treatment (P = 0.036), but not afterwards. Patients treated with enalapril had a higher risk of dizziness or hypotension (RR 7.17, 95% CI 1.71 to 30.17) and fatigue (Fisher's exact test, P = 0.013).The RCT on phosphocreatine found no differences in overall survival, mortality due to heart failure, echocardiographic cardiac function and adverse events between treatment and control group. AUTHORS' CONCLUSIONS: For the effect of enalapril in childhood cancer survivors with asymptomatic cardiac dysfunction, only one RCT is available. Although there is some evidence that enalapril temporarily improves one parameter of cardiac function (LVESWS), it is unclear whether it improves clinical outcomes. Enalapril was associated with a higher risk of dizziness or hypotension and fatigue. Clinicians should weigh the possible benefits with the known side-effects of enalapril in childhood cancer survivors with asymptomatic anthracycline-induced cardiotoxicity.For the effect of phosphocreatine in childhood cancer patients with anthracycline-induced cardiotoxicity, only one RCT is available. Limited data with a high risk of bias showed no significant difference between phosphocreatine and control treatment on echocardiographic function and clinical outcomes.We did not identify any RCTs or CCTs studying other medical interventions for symptomatic or asymptomatic cardiotoxicity in childhood cancer patients or survivors.High-quality studies should be performed.

Hepatic late adverse effects after antineoplastic treatment for childhood cancer.

BACKGROUND: Survival rates have greatly improved as a result of more effective treatments for childhood cancer. Unfortunately the improved prognosis has resulted in the occurrence of late, treatment-related complications. Liver complications are common during and soon after treatment for childhood cancer. However, among long-term childhood cancer survivors the risk of hepatic late adverse effects is largely unknown. To make informed decisions about future cancer treatment and follow-up policies it is important to know the risk of, and associated risk factors for, hepatic late adverse effects. OBJECTIVES: To evaluate the existing evidence on the association between antineoplastic treatment for childhood cancer and hepatic late adverse effects. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 2), MEDLINE (1966 to June 2009) and EMBASE (1980 to June 2009). In addition, we searched reference lists of relevant articles and conference proceedings. SELECTION CRITERIA: All studies except case reports, case series and studies including less than 10 patients that examined the association between antineoplastic treatment for childhood cancer (aged 18 years or less at diagnosis) and hepatic late adverse effects (one year or more after the end of treatment). DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection, risk of bias assessment and data extraction. MAIN RESULTS: We identified 20 cohort studies investigating hepatic late adverse effects after antineoplastic treatment for childhood cancer. All studies had methodological limitations. The prevalence of hepatic late adverse effects varied widely, between 0% and 84.2%. Selecting studies where the outcome of hepatic late adverse effects was well defined as alanine aminotransferase (ALT) above the upper limit of normal resulted in five studies. In this subgroup the prevalence of hepatic late adverse effects ranged from 8.0% to 52.8%, with follow-up durations varying from one to 27 years after the end of treatment. A more stringent selection process using the outcome definition of ALT as above twice the upper limit of normal resulted in three studies, with a prevalence ranging from 7.9% to 44.8%. Chronic viral hepatitis was identified as a risk factor for hepatic late adverse effects in univariate analyses. It is unclear which specific antineoplastic treatments increase the risk of hepatic late adverse effects AUTHORS' CONCLUSIONS: The prevalence of hepatic late adverse effects ranged from 7.9% to 52.8% when selecting studies with an adequate outcome definition. It has not been established which childhood cancer treatments result in hepatic late adverse effects. There is a suggestion that chronic viral hepatitis increases the risk of hepatic late adverse effects. More well-designed studies are needed to reliably evaluate the prevalence of, and risk factors for, hepatic late adverse effects after antineoplastic treatment for childhood cancer.

Different anthracycline derivates for reducing cardiotoxicity in cancer patients.

BACKGROUND: The use of anthracyclines is limited by the occurrence of cardiotoxicity. In an effort to prevent this cardiotoxicity, different anthracycline derivates have been studied. OBJECTIVES: To determine the occurrence of cardiotoxicity with the use of different anthracycline derivates in cancer patients. SEARCH STRATEGY: We searched The Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 2, 2009), MEDLINE (1966 to 29 May 2009) and EMBASE (1980 to 2 June 2009). 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 study selection, assessment of risk of bias 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 (epirubicin versus liposomal-encapsulated doxorubicin) or no 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.

Cyclophosphamide versus ifosfamide for paediatric and young adult bone and soft tissue sarcoma patients.

BACKGROUND: Alkylating agents, such as cyclophosphamide and ifosfamide, play a major role in the improved survival of children and young adults with bone and soft tissue sarcoma. However, there is still controversy as to their comparative anti-tumour efficacy and possible adverse effects. OBJECTIVES: To compare the possible effectiveness of cyclophosphamide with that of ifosfamide for paediatric and young adult patients with sarcoma. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library 2008, issue 4), MEDLINE/PubMed (from 1966 to November 2008) and EMBASE/Ovid (from 1980 to November 2008) with pre-specified terms. In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trial databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing cyclophosphamide and ifosfamide for the treatment of different types of sarcoma in paediatric and young adult patients (aged less than 30 years at diagnosis). Chemotherapy other than either cyclophosphamide or ifosfamide should have been the same in both treatment groups. DATA COLLECTION AND ANALYSIS: Two authors independently performed the study selection. MAIN RESULTS: No studies meeting the inclusion criteria of the review were identified. AUTHORS' CONCLUSIONS: No RCTs or CCTs comparing the effectiveness of cyclophosphamide and ifosfamide in the treatment of bone and soft tissue sarcoma in children and young adults were identified. Therefore no definitive conclusions can be made about the effects of cyclophosphamide and ifosfamide in these patients. Based on the currently available evidence we are not able to give recommendations for clinical practice. More high quality research is needed.

Different anthracycline derivates for reducing cardiotoxicity in cancer patients.

BACKGROUND: The use of anthracyclines is limited by the occurrence of cardiotoxicity. In an effort to prevent this cardiotoxicity, different anthracycline derivates have been studied. OBJECTIVES: To determine the occurrence of cardiotoxicity with the use of different anthracycline derivates in cancer patients. SEARCH STRATEGY: We searched The Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 2, 2009), MEDLINE (1966 to 29 May 2009) and EMBASE (1980 to 2 June 2009). 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 study selection, assessment of risk of bias 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 (epirubicin versus liposomal-encapsulated doxorubicin) or no 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.

High-dose chemotherapy and autologous haematopoietic stem cell rescue for children with high-risk neuroblastoma.

BACKGROUND: Despite the development of new treatment options, the prognosis of high-risk neuroblastoma patients is still poor; more than half of patients experience disease recurrence. High-dose chemotherapy and haematopoietic stem cell rescue (i.e. myeloablative therapy) might improve survival. OBJECTIVES: To compare the effectiveness of myeloablative therapy with conventional therapy in children with high-risk neuroblastoma. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library 2009, issue 1), MEDLINE/PubMed (1966 to January 2009) and EMBASE/Ovid (1980 to January 2009). In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trial databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the effectiveness of myeloablative therapy with conventional therapy in high-risk neuroblastoma patients. DATA COLLECTION AND ANALYSIS: Two authors independently performed study selection, data extraction and risk of bias assessment. If possible, we pooled results. MAIN RESULTS: We identified three RCTs including 739 children. The meta-analysis of event-free survival showed a significant difference in favour of the myeloablative therapy group (HR 0.78; 95% CI 0.67 to 0.90), as did the meta-analysis of overall survival (HR 0.74; 95% CI 0.57 to 0.98). The meta-analysis of secondary malignant disease and treatment-related death did not show a significant difference between the treatment groups. In one study a significant difference in favour of the conventional therapy group was identified for renal effects, interstitial pneumonitis and veno-occlusive disease, whereas for serious infections and sepsis no significant difference between the treatment groups was identified. In the individual studies we evaluated different subgroups, but the results were not univocal in all studies. All studies had some methodological limitations. AUTHORS' CONCLUSIONS: Based on the currently available evidence, myeloablative therapy seems to be a good treatment option for children with high-risk neuroblastoma. It results in higher survival rates than conventional therapy, although possible higher levels of adverse effects should be kept in mind. A definitive conclusion regarding the effect of myeloablative therapy in different subgroups is not possible. This systematic review only allows a conclusion on the concept of myeloablative therapy; no conclusions can be made regarding the best treatment strategy. Future trials on the use of myeloablative therapy for high-risk neuroblastoma should focus on identifying the most optimal induction and/or myeloablative regimen. The best study design to answer these questions is a RCT. These RCTs should be performed in homogeneous study populations (for example, regarding stage of disease and patient age) and have a long-term follow up. Different risk groups should be taken into account.

High-dose chemotherapy for children and young adults with stage IV rhabdomyosarcoma.

BACKGROUND: Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Prognosis for patients with metastatic disease has not improved significantly in the past decades. High-dose chemotherapy (HDC) seems to be an attractive option to treat minimal residual disease in metastatic rhabdomyosarcoma patients. OBJECTIVES: The objective of the review was to assess the effectiveness of HDC with stem cell rescue (SRC) versus standard-dose chemotherapy in improving event-free survival (EFS) and overall survival (OS) of children and young adults with metastatic rhabdomyosarcoma. SEARCH STRATEGY: We searched the databases of MEDLINE (1966 to December 2009), EMBASE (1980 to December 2009) and CENTRAL (The Cochrane Library Issue 1, 2009). In addition, we handsearched the reference lists of selected papers and conference proceedings of the SIOP, ASPHO and ASCO meetings (all 2000 to 2009). SELECTION CRITERIA: Randomised controlled trials (RCT), prospective or historical controlled clinical trials (CCT), in which HDC with SCR was compared to conventional chemotherapy and prospective case series (non-controlled clinical trials) including at least 20 naive metastatic rhabdomyosarcoma patients DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection, quality assessment and data extraction. MAIN RESULTS: No RCTs could be identified. We identified one prospective CCT, one retrospective CCT and one non-controlled clinical trial. Another CCT has been published as an abstract. All studies have severe methodological limitations, in particular selection bias could not be excluded. One CCT reported a significantly worse OS compared to oral maintenance therapy, however in a subgroup of high-risk patients no difference could be found. The retrospective CCT reported a similar survival for HDC compared to conventional chemotherapy. The non-controlled clinical trial and the CCT reported as a conference proceeding reported survival outcomes comparable to previous studies. Data on toxicity showed more grade 3-4 toxicity in the HDC group. However, there was no difference in the number of toxic deaths. AUTHORS' CONCLUSIONS: Overall, the results of this review do not justify the use of HDC with SCR as a standard therapy for children with metastatic rhabdomyosarcoma. However, all reported studies were possibly subject to significant bias, especially selection bias. This might have underestimated the measured effect of HDC. As a result, a clinically important excess of adverse risk patients in the HDC arms may explain the non-beneficial effect of HDC. Only a large prospective RCT will be able to answer the question of whether HDC with SCR adds to survival or not definitively.

Minimally invasive surgery versus open surgery for the treatment of solid abdominal and thoracic neoplasms in children.

BACKGROUND: Minimally invasive surgery (MIS) is an accepted surgical technique for the treatment of a variety of benign diseases. Presently, the use of MIS in patients with cancer is progressing. However, the role of MIS in children with solid neoplasms is less clear than it is in adults. Diagnostic MIS to obtain biopsy specimens for pathology has been accepted as a technique in paediatric surgical oncology, but there is limited experience with the use of MIS for the resection of malignancies. OBJECTIVES: To ascertain the differences in outcome between the minimally invasive and open approach in the treatment of solid intra-thoracic and intra-abdominal neoplasms in children, regarding overall survival, event-free survival, port-site metastases, recurrence rate and surgical morbidity. SEARCH STRATEGY: We searched the electronic databases of MEDLINE/PubMed (from 1966 to March 2008), EMBASE/Ovid (from 1980 to March 2008) and CENTRAL (The Cochrane Library 2008, Issue 1) with pre-specified terms. In addition, we searched reference lists of relevant articles and reviews, conference proceedings and ongoing trial databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing MIS and open surgery for the treatment of solid intra-thoracic or intra-abdominal neoplasms in children (aged 0 to 18 years). DATA COLLECTION AND ANALYSIS: Two authors performed the study selection independently. MAIN RESULTS: No studies that met the inclusion criteria of this review were identified. AUTHORS' CONCLUSIONS: No RCTs or CCTs evaluating MIS in the treatment of solid intra-thoracic or intra-abdominal neoplasms in children could be identified, therefore no definitive conclusions could be made about the effects of MIS in these patients. Based on the currently available evidence we are not able to give recommendations for the use of MIS in the treatment of solid intra-thoracic or intra-abdominal neoplasms in children. More high quality studies (RCTs and/or CCTs) are needed. To accomplish this, centres specialising in MIS in children should collaborate.

Influenza vaccination in children being treated with chemotherapy for cancer.

BACKGROUND: Influenza infection is a potential cause of severe morbidity in children with cancer, therefore vaccination against influenza is recommended. However, there are conflicting data concerning the immune response to influenza vaccination in children with cancer and the value of vaccination remains unclear. OBJECTIVES: 1. To assess the efficacy of influenza vaccination in stimulating immunological response in children with cancer during chemotherapy, compared to control groups. 2. To assess the efficacy of influenza vaccination in preventing confirmed influenza and influenza-like illness and/or stimulating immunological response in children with cancer treated with chemotherapy, compared to placebo, no intervention or different dosage schedules. 3. To determine the adverse effects associated with influenza vaccination in children with cancer. SEARCH STRATEGY: We searched CENTRAL, MEDLINE (1966 to 2007) and EMBASE (1980 to 2007) up to February 2007. We also searched reference lists of relevant articles and conference proceedings of ICAAC, IDSA, MASCC and SIOP. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) and controlled clinical trials (CCTs) in which the serologic response to influenza vaccination of children with cancer was compared to other control groups. We also considered RCTs and CCTs comparing the effects of influenza vaccination on clinical response and/or immunological response in children with cancer, with placebo, no intervention or different dosage schedules. DATA COLLECTION AND ANALYSIS: Two independent authors assessed the methodological quality of included studies and extracted data. MAIN RESULTS: We included 1 RCT and 8 CCTs ( total number of participants=708). None of the included studies reported on clinical outcome. All included studies reported on influenza immunity and adverse reactions to vaccination. In five studies, immune responses to influenza vaccine were compared in 272 children on chemotherapy with 166 children not on chemotherapy. In three studies, responses to influenza vaccine were assessed in 204 children on chemotherapy compared with responses in 112 healthy children. The measures used to assess immune responses were: a four-fold rise in antibody titre after vaccination, development of haemagglutination inhibition (HI) titre > 32, and pre- and post-vaccination geometric mean titres (GMT). Immune responses in children receiving chemotherapy were consistently weaker (four-fold rise of 25% to 52%) than in those children who had completed chemotherapy (50% to 86%) and in healthy children (71% to 89%). Concerning adverse effects, 359 paediatric oncology patients received influenza vaccine and the side effects described were mild local reactions and low grade fever. No life-threatening or persistent adverse effects were reported. AUTHORS' CONCLUSIONS: Paediatric oncology patients receiving chemotherapy are able to generate an immune response to the influenza vaccine, but it remains unclear whether this immune response protects them from influenza infection or its complications. We are awaiting results from well-designed RCTs addressing the clinical benefit of influenza vaccination in these patients.

Treatment including anthracyclines versus treatment not including anthracyclines for childhood cancer.

BACKGROUND: One of the most important adverse effects of anthracyclines is cardiotoxicity. A well-informed decision on the use of anthracyclines in the treatment of different types of childhood cancer should be based on the available evidence on both antitumour efficacy and cardiotoxicity. OBJECTIVES: To compare antitumour efficacy of treatment including or not including anthracyclines in children with childhood cancer. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2006, issue 4), MEDLINE (1966 to January 2007) and EMBASE (1980 to January 2007). In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trials databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing treatment of any type of childhood cancer with and without anthracyclines and reporting outcomes concerning antitumour efficacy. DATA COLLECTION AND ANALYSIS: Two reviewers independently performed the study selection, quality assessment and data-extraction. MAIN RESULTS: We identified RCTs for 5 types of tumour: acute lymphoblastic leukaemia (ALL) (n=3; 912 children), Wilms' tumour (n=1; 316 children), rhabdomyosarcoma/undifferentiated sarcoma (n=1; 413 children), Ewing's sarcoma (n=1; 94 children), and non-Hodgkin lymphoma (n=1; 284 children). All studies had methodological limitations. For ALL no evidence of a significant difference in antitumour efficacy was identified in the meta-analyses, but in most individual studies there was a suggestion of better antitumour efficacy in patients treated with anthracyclines. For both Wilms' tumour and Ewing's sarcoma a significant difference in survival in favour of treatment with anthracyclines was identified. The hazard ratios for overall and event-free survival in Wilms' tumour were 1.85 (95% CI 1.09 to 3.15) and 2.21 (95% CI 1.44 to 3.40), respectively. For patients with Ewing's sarcoma only descriptive results were available (P = 0.02 for overall survival and P = 0.01 for event-free survival). For both rhabdomyosarcoma/undifferentiated sarcoma and non-Hodgkin lymphoma no difference in antitumour efficacy between the treatment groups was identified. Clinical cardiotoxicity was evaluated in 3 RCTs. No significant difference between both treatment groups was identified, but in all individual studies there was a suggestion of a lower rate of clinical cardiotoxicity in patients who did not receive anthracyclines. None of the studies evaluated asymptomatic cardiac dysfunction. For other childhood cancers no RCTs were identified. AUTHORS' CONCLUSIONS: At the moment no evidence from RCTs is available which underscores the use of anthracyclines in ALL. However, it should be noted that "no evidence of effect", as identified in this review, is not the same as "evidence of no effect". For Wilms' tumour, rhabdomyosarcoma/undifferentiated sarcoma, Ewing's sarcoma, and non-Hodgkin lymphoma only 1 RCT was available and therefore, no definitive conclusions can be made about the antitumour efficacy of treatment with or without anthracyclines in these tumours. For other childhood cancers no RCTs were identified and therefore, no conclusions can be made about the antitumour efficacy of treatment with or without anthracyclines in these tumours. More high quality research is needed.

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. To prevent this cardiotoxicity, different anthracycline dosage schedules have been studied. OBJECTIVES: To determine the occurrence of cardiotoxicity with the use of different anthracycline dosage schedules (i.e. peak doses and infusion durations) in cancer patients. SEARCH STRATEGY: We searched the databases of The Cochrane Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 4, 2008), MEDLINE (1966 to November 2008) and EMBASE (1980 to November 2008). Also, 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, the risk of bias assessment and the data-extraction. MAIN RESULTS: We identified seven RCTs addressing different anthracycline infusion durations. 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 (relative risk (RR) = 0.27; 95% confidence interval (CI) 0.09 to 0.81; 5 studies; 557 patients). The majority of patients included in these studies were adults with different solid tumours. For different anthracycline peak doses we identified two RCTs addressing a doxorubicin peak dose of less than 60 mg/m(2) versus 60 mg/m(2) or more, one RCT addressing a liposomal doxorubicin peak dose of 25 mg/m(2) versus 50 mg/m(2) and one RCT addressing an epirubicin peak dose of 83 mg/m(2) versus 110 mg/m(2). In none of the studies a significant difference in the occurrence of clinical heart failure was identified. All patients included in these studies were adults with different solid tumours. 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. Since there is only a small amount of data for children and data obtained in adults cannot be extrapolated to children, different anthracycline infusion durations should be evaluated further in children.No significant difference in the occurrence of clinical heart failure was identified in patients treated with a doxorubicin peak dose of less than 60 mg/m(2) or 60 mg/m(2) or more. For the other identified peak doses only one RCT was available, so no definitive conclusions can be made about the occurrence of cardiotoxicity. More high quality research is needed, both in children and adults and in leukaemias and solid tumours.

Report on the international colloquium on cardio-oncology (rome, 12-14 march 2014).

Cardio-oncology is a relatively new discipline that focuses on the cardiovascular sequelae of anti-tumour drugs. As any other young adolescent discipline, cardio-oncology struggles to define its scientific boundaries and to identify best standards of care for cancer patients or survivors at risk of cardiovascular events. The International Colloquium on Cardio-Oncology was held in Rome, Italy, 12-14 March 2014, with the aim of illuminating controversial issues and unmet needs in modern cardio-oncology. This colloquium embraced contributions from different kind of disciplines (oncology and cardiology but also paediatrics, geriatrics, genetics, and translational research); in fact, cardio-oncology goes way beyond the merging of cardiology with oncology. Moreover, the colloquium programme did not review cardiovascular toxicity from one drug or the other, rather it looked at patients as we see them in their fight against cancer and eventually returning to everyday life. This represents the melting pot in which anti-cancer therapies, genetic backgrounds, and risk factors conspire in producing cardiovascular sequelae, and this calls for screening programmes and well-designed platforms of collaboration between one key professional figure and another. The International Colloquium on Cardio-Oncology was promoted by the Menarini International Foundation and co-chaired by Giorgio Minotti (Rome), Joseph R Carver (Philadelphia, Pennsylvania, United States), and Steven E Lipshultz (Detroit, Michigan, United States). The programme was split into five sessions of broad investigational and clinical relevance (what is cardiotoxicity?, cardiotoxicity in children, adolescents, and young adults, cardiotoxicity in adults, cardiotoxicity in special populations, and the future of cardio-oncology). Here, the colloquium chairs and all the session chairs briefly summarised what was said at the colloquium. Topics and controversies were reported on behalf of all members of the working group of the International Colloquium on Cardio-Oncology.