|
Frequency and risk factors of subclinical cardiotoxicity after anthracycline therapy in children: a systematic review |
Kremer L C, van der Pal H J, Offringa M, van Dalen E C, Voute P A |
|
|
Authors' objectives To determine the frequency and risk factors of subclinical cardiotoxicity in apparently healthy survivors of childhood cancer after anthracycline therapy.
Searching MEDLINE was searched from 1966 to May 2001. Full details of the search strategy were reported. The bibliographies of all relevant articles and reviews were examined for additional references. Only publications in the English language were eligible.
Study selection Study designs of evaluations included in the reviewOnly studies of original research with a study population of greater than 50 children were eligible for inclusion. Longitudinal studies and transverse studies were included. The duration of follow-up ranged from the end of treatment to 23.4 years.
Specific interventions included in the reviewStudies of anthracycline therapy (doxorubicin, daunorubicin or epirubicin) for childhood cancer were eligible. The cumulative anthracycline dose ranged from 19 to 1,275 mg/m2. The proportion of patients who also had radiotherapy to the heart region ranged from 0 to 34% across the studies.
Participants included in the reviewChildren with cancer were eligible for inclusion. The participants' age at diagnosis, where stated, ranged from 0.2 to 28.9 years. The studies included patients with various tumours such as Hodgkin's disease, Wilm's tumour, osteosarcoma, Ewing sarcoma, soft tissue sarcoma, leukaemia (including acute lymphoblastic leukaemia) and rhabdomyosarcoma.
Outcomes assessed in the reviewStudies that assessed subclinical cardiotoxicity were eligible for inclusion. The included studies defined subclinical cardiotoxicity as an abnormal systolic function, as measured using echocardiography or radionuclide angiocardiography or as an increased afterload measured by echocardiography. The studies also assessed systolic function of the left ventricle using shortening fraction, ejection fraction, the fibre-shortening velocity corrected for heart rate, the stress-velocity index, end-systolic wall stress, left ventricular posterior wall thickness in diastole and systole, left ventricular diastolic and systolic diameter, and left ventricular mass. The included studies defined the outcome as abnormal compared with normal values from the literature or their own control groups.
How were decisions on the relevance of primary studies made?Two reviewers initially assessed relevance based on title and abstract (inter-observer agreement was 98%). Two reviewers then screened all retrieved articles with respect to the inclusion criteria. Any disagreements were resolved by re-examining and discussing the articles until consensus was reached. Inter-observer agreement was 96% with respect to the application of the inclusion criteria.
Assessment of study quality Validity was assessed according to the criteria described by Laupacis et al. (see Other Publications of Related Interest). In this review the sample was considered 'well-defined' if the mean, median or range of the cumulative anthracycline dose was reported; the sample was considered 'representative' if the sample included greater than 95% of the whole cohort from the start of therapy, the cohort of survivors or a random sample of patients with respect to the cumulative dose. The follow-up was considered 'adequate' if the minimal follow-up was more than 1 year after the end of chemotherapy or the median follow-up was 2 years; the follow-up was considered 'complete' if the outcome was assessed at the end-of-study date for more than 95% of the study population. It was also assessed whether the original cohort could be identified, whether patients had entered the cohort at a similar well-defined point in the course of disease, whether there were 'objective and unbiased outcome criteria', and whether there was adjustment for important prognostic factors. Each study was graded as meeting or not meeting the criteria, and a validity score awarded (range 0 to 8). Two reviewers assessed validity. Any disagreements were resolved by re-examining and discussing the articles until consensus was reached.
Data extraction Two reviewers extracted the following data: study population details, possible risk factors such as cumulative dose of anthracycline, dose within 1 week, age at diagnosis, gender distribution, radiation therapy to the heart region, duration of follow-up, method of detection and frequency of subclinical cardiotoxicity. Any disagreements were resolved by re-examining and discussing the articles until consensus was reached. The frequency of subclinical cardiotoxicity was calculated as the number of patients with an abnormal systolic function divided by the number of patients in the study group. The 95% confidence interval for the frequency was also calculated. Data on the risk factors included in multivariate analyses in some of the studies were presented.
Methods of synthesis How were the studies combined?A narrative synthesis was undertaken.
How were differences between studies investigated?The frequency of subclinical cardiotoxicity was discussed with respect to the criteria used to diagnose subclinical cardiotoxicity, validity and the dose of anthracycline used.
Results of the review Twenty-five studies (2,563 patients) were included. There was one longitudinal study until the end of treatment (125 children) and 24 transverse studies in survivors only.
There were 8 studies of doxorubicin, 2 of daunorubicin and 15 of a combination of anthracyclines. Eleven studies described a mean or median anthracycline dose of less than 300 mg/m2. Three studies only reported the range of anthracyclines.
All studies had methodological limitations. Fourteen studies had serious limitations (validity score less than 5). The methodological problems included: follow-up less than 95% of the original cohort of survivors (23 studies were of a subgroup of the original cohort of survivors, and in only 4 of these studies was the subgroup representative of the original cohort); the number of patients in the original cohort was not reported (15 studies); a lack of clarity about whether systolic function was assessed in all patients (15 studies); only 5 studies reported that the outcome assessor was blinded to possible risk factors; and only 10 studies adjusted for potential confounders.
The reported frequency of subclinical cardiotoxicity ranged from 0% to 57.4%. The studies differed in the outcome definitions of subclinical cardiotoxicity and in study patients with respect to anthracycline dose.
Fifteen studies defined abnormal systolic function as an abnormal shortening fraction. The lower limit of normal of the SF ranged from 28 to 30%. Six studies with validity scores of greater than 5 reported frequencies of subclinical cardiotoxicity ranging from 0 to 27.8%. The range of frequency of abnormal shortening fraction appeared to be higher for patients treated with a mean or median cumulative anthracycline dose of greater than 300 mg/m2 (15.5 to 27.8%) than for patients treated with a smaller cumulative dose of less than 300 mg/m2 (0 to 15.2%).
Risk factors (10 studies): increased risk factors for a decreased systolic function and for an increased afterload included a higher cumulative dose, longer follow-up time, mediastinal radiation, female gender, higher dose in 3 weeks, diagnosis, and lower (2 studies) and older (1 study) age at diagnosis.
Authors' conclusions The reported frequency of subclinical cardiotoxicity shows a wide variation. Well-designed studies with accurate and precise outcomes 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.
CRD commentary The aims of the review were stated and the inclusion criteria were defined in terms of the participants, interventions, sample size and outcomes. By restricting the included studies to reports published in English, as identified in one database, some other relevant studies may have been omitted and the possibility of publication bias cannot be excluded. The methods used to select the studies were described and inter-observer agreement was assessed. Validity was formally assessed using validated criteria and the methods used to assess validity were described. Relevant information on the individual studies was tabulated and details of the methods used to extract the data were given. A narrative synthesis was appropriate in view of the heterogeneity among the studies, and potential reasons for this heterogeneity were explored and discussed in the text of the review. The evidence presented supports the authors' conclusions.
Implications of the review for practice and research Practice: The authors did not state any implications for practice.
Research: The authors state that more cohort studies and randomised trials are needed to investigate the factors that increase the risk of subclinical cardiotoxicity after anthracycline therapy in children. They further state that such studies should focus on cardiotoxic effects of different types of anthracyclines, cumulative dose, dose intensity, and the cardiotoxic effect of cointerventions weighted against the benefit of anthracyclines on survival. The studies should be conducted in well-defined and representative patient groups from the start of treatment, or in survivors with a complete and sufficient length of follow-up, and include precise and accurate outcome measures. Patients with cardiotoxicity should be monitored for a long period to obtain insight into the clinical consequences.
Bibliographic details Kremer L C, van der Pal H J, Offringa M, van Dalen E C, Voute P A. Frequency and risk factors of subclinical cardiotoxicity after anthracycline therapy in children: a systematic review. Annals of Oncology 2002; 13(6): 819-829 Other publications of related interest Laupacis A, Wells G, Richardson WS, Tugwell P. Users' guides to the medical literature. V. How to use an article about prognosis. Evidence-Based Medicine Working Group. JAMA 1994;272:234-7.
Indexing Status Subject indexing assigned by NLM MeSH Antibiotics, Antineoplastic /adverse effects /therapeutic use; Cardiomyopathies /chemically induced /epidemiology /physiopathology; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Neoplasms /diagnosis /drug therapy; Netherlands /epidemiology; Prognosis; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Severity of Illness Index; Survival Rate AccessionNumber 12002001638 Date bibliographic record published 31/08/2003 Date abstract record published 31/08/2003 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
|
|
|