Types of studies

Randomized controlled trials (RCTs) and controlled clinical trials (CCTs) (as defined by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008)), including non‐inferiority and cross‐over trials, comparing a medical intervention for treating anthracycline‐induced cardiotoxicity with either placebo, other medical intervention(s) or no treatment.

Types of participants

Patients and survivors (previously) diagnosed with any type of childhood cancer (defined as a diagnosis of cancer at age 18 years or younger) and with symptomatic or asymptomatic anthracycline‐induced cardiotoxicity. RCTs or CCTs including both children and adults are only eligible for inclusion in this review if the majority of participants are 18 years or younger at cancer diagnosis. Anthracycline‐induced cardiotoxicity, as defined by the authors of the original study, can be diagnosed both during and after anthracycline treatment for childhood cancer. Due to the low number of patients expected, we will not exclude patients who have also been treated with mediastinal radiotherapy.

Types of interventions

Medical (i.e. drug) interventions given with the intention to change the course of anthracycline‐induced symptomatic or asymptomatic cardiotoxicity. We will exclude surgical interventions such as heart transplantation.

Types of outcome measures

Electronic searches

We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue), MEDLINE/PubMed (from 1949 onwards) and EMBASE/Ovid (from 1980 onwards) for potentially relevant articles.

We will scan the ISRCTN Register, the National Institute of Health (NIH) Register and the trials register of the World Health organization (WHO) for ongoing trials (http://www.controlled‐trials.com and http://apps.who.int/trialsearch/). We will contact experts in the field for information on possible relevant trials.

There will be no language restriction. All electronic searches have been developed in co‐operation with the Trials Search Co‐ordinator of the Cochrane Childhood Cancer Group.

The search strategy for PubMed is shown in Appendix 1. We will use the highly sensitive search strategy for identifying reports of RCTs and CCTs (sensitivity‐maximizing version) as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008).

For EMBASE and CENTRAL we will use adaptations of the same search strategy (see Appendix 2, Appendix 3).

Searching other resources

We will locate information about trials not registered in MEDLINE/PubMed, EMBASE/Ovid or CENTRAL, either published or unpublished, by searching the reference lists of relevant articles and review articles. In addition, we will handsearch conference proceedings from 2004 to 2008 of the International Society for Paediatric Oncology (SIOP), the American Society of Clinical Oncology (ASCO), the American Society of Hematology (ASH), the International Conference on Long‐Term Complications of Treatment of Children & Adolescents for Cancer and the European Symposium on Late Complications from Childhood Cancer. Again, there will be no language restrictions.

Selection of studies

After employing the search strategy described previously, two independent authors will undertake identification of studies meeting the criteria for this review. We will resolve discrepancies between authors by consensus. If this is impossible, we will achieve final resolution using a third‐party arbitrator. We will obtain in full any study which seems to meet the inclusion criteria on the grounds of the title, abstract or both for closer inspection. We will clearly state reasons for exclusion of any study considered for the review. In cases of double publication only one study will be included.

Data extraction and management

Two independent authors will abstract from each study information about the study characteristics, participants, interventions, duration of follow up and outcome parameters using standardized forms. We will extract data on the following items:

1. study design;

2. quality items;

3. number of study patients;

4. participants, including:

   1. age at diagnosis;

   2. age at study entry;

   3. sex;

   4. time since diagnosis;

   5. study performed during cancer treatment or in survivors;

   6. in case of survivors, time since end of cancer treatment;

   7. prior anthracycline treatment, including:

      1. type of anthracycline;

      2. cumulative anthracycline dose;

   8. other previous treatment, including:

      1. chemotherapy;

      2. cardioprotective interventions;

      3. radiotherapy on heart region;

   9. co‐morbidities, including:

      1. cardiovascular disease (specification disease, cause and duration of disease before start of intervention);

      2. other (specification disease, cause and duration of disease before start of intervention);

   10. other treatment, including:

       1. other cardiovascular medication (agent, dose, frequency, mode of administration and duration);

       2. other medication (agent, dose, frequency, mode of administration and duration);

       3. cardiovascular surgery (location and procedure);

5. interventions, including:

   1. type of medical intervention (substance name, brand name);

   2. dose and frequency of medical intervention;

   3. mode of administration (oral, intravenous etc.);

   4. duration of medical intervention;

   5. duration between diagnosis of anthracycline‐induced cardiotoxicity and start of medical intervention;

6. outcome measures, including:

   1. outcome definition;

   2. timing of outcome measurement;

7. length of follow up.

In cases of disagreement, we will re‐examine the abstracts and articles and undertake discussion until consensus is achieved. If this is impossible, we will achieve final resolution using a third‐party arbitrator.

Assessment of risk of bias in included studies

To assess risk of bias in the selected studies, two independent authors will assess the design and execution of each study according to the following criteria: concealment of treatment allocation, blinding of the care provider, blinding of the patients, blinding of the outcome assessor, intention‐to‐treat analysis and completeness of follow up. For all quality items we will use the definitions as described in the guidelines of the Cochrane Childhood Cancer Group (Module CCG), which is based on the Cochrane Handbook for Systematic Reviews of Interventions section on risk of bias. We will resolve discrepancies between authors by consensus. If this is impossible, we will achieve final resolution using a third‐party arbitrator.

In the analyses, we will take the quality of studies into account in the interpretation of the review’s results.

Measures of treatment effect

We will analyse dichotomous outcomes using risk ratio (RR); we will analyse continuous outcomes using the weighted mean difference (WMD). We will present all results with the corresponding 95% confidence interval (CI). For the assessment of survival, we will use Parmar’s method if hazard ratios have not been explicitly presented in the study (Parmar 1998).

Dealing with missing data

When information relevant to study selection, data extraction and/or assessment of risk of bias is missing, we will attempt to contact the authors in order to obtain the missing data.

We will extract data by allocation intervention, irrespective of compliance with the allocated intervention, in order to allow an intention‐to‐treat analysis. If this is not possible, this will be stated and we will perform an 'as treated' analysis.

Assessment of heterogeneity

We will assess heterogeneity both by visual inspection of forest plots and by a formal statistical test for heterogeneity, i.e. the I² statistic. Substantial heterogeneity is defined as I² > 50% (Higgins 2008). We will explore possible reasons for the occurrence of heterogeneity and take appropriate measures. We will use a random‐effects model throughout the review.

Assessment of reporting biases

We will construct a funnel plot to ascertain the existence of publication bias graphically (Higgins 2008).

Data synthesis

The data will be entered into RevMan 5.0 (RevMan 2008) and analysed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008).

We will include outcome measures in this systematic review only if it was the intention of the study authors to perform the necessary assessments in all randomized patients (i.e. not optional or only performed in some centres). When less than 50% of the patients in a study have an acceptable follow up for a particular outcome measure, due to the associated high risk of attrition bias we will not report the results of this outcome measure.

If the included studies are of good methodological quality and if the various study groups are comparable with regard to age, sex, cardiac dysfunction, treatment, used outcome definitions and length of follow up, we will perform a pooled analysis. Otherwise we will summarise the results qualitatively. We will analyse data separately, if possible, for clinical heart failure alone versus no clinical heart failure, and for clinical and subclinical cardiotoxicity combined versus normal heart function.

Subgroup analysis and investigation of heterogeneity

Treatment with mediastinal radiotherapy may cause other cardiac pathology, such as heart valve problems. It is therefore possible that treatment effects differ between patients treated with and without mediastinal radiotherapy. If the included studies are of good methodological quality and if the various study groups are comparable with regard to age, sex, cardiac dysfunction, treatment, used outcome definitions and length of follow up, we will investigate this type of heterogeneity by performing a subgroup analysis with regard to previous mediastinal radiotherapy. This will be done using the significance test as described by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008).

Sensitivity analysis

We will perform a sensitivity analysis using quality criteria.