Clinical heart failure in children, adolescents and young adults treated with anthracyclines and/or irradiation involving the heart region

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To evaluate the existing evidence for an association between childhood, adolescent and young adult cancer treatment with anthracyclines and/or irradiation involving the heart region and the occurrence of both early and late clinical heart failure (CHF).

Background

In children leukaemia is the most common malignancy, followed by central nervous system (CNS) tumours, sarcomas and lymphoma (Robinson 2002). Around 60% of children with cancer receive anthracyclines (doxorubicin, daunorubicin, epirubicin and/or idarubicin) as part of the treatment. Roughly 20% of the children will get irradiation involving the heart region (i.e., total body irradiation, left or whole abdominal irradiation, spinal irradiation and thoracic irradiation) (Van der Pal 2012). Anthracyclines and irradiation are effective treatment modalities; however, both have been associated with deterioration of cardiac function (Cohn 1967; Gagliardi 2010; Von Hoff 1979; Lipshultz 2005). Anthracycline- and irradiation-associated heart failure (HF) can show as either diastolic or systolic dysfunction (Brouwer 2011), and may progress to either dilated or constricted cardiomyopathy (Lipshultz 2005). Cardiac dysfunction can be asymptomatic or symptomatic (Kremer 2002a; Kremer 2002b). It can occur not only during therapy, but also years after its completion (Van Dalen 2006). Clinical anthracycline- and irradiation-associated HF is a well-known problem in children; the incidence of clinical heart failure (CHF) has been reported to be as high as 16% at 0.9 to 4.8 years after treatment (anthracycline-associated), and between 0.3 to 22.8% up to 26.5 years after treatment (irradiation-associated) (Kremer 2002a; Van der Pal 2005).This review will focus on CHF. Although the mechanism of anthracycline-associated CHF is not fully understood, it is clear that free radicals play an important role in damaging cardiac myocyte membranes (Horenstein 2000). The cause of irradiation-associated HF is microvascular changes, which result in fibrosis mainly in the interstitial part of the myocardium. This may cause reduced contractility and thus a combination of diastolic and systolic dysfunction. Irradiation involving the heart region also affects other parts of the heart, including the pericardium, valves, coronaries and conduction system (Van der Pal 2012). Risk factors for developing anthracycline-associated and irradiation-associated CHF are contradictory in the literature (Kremer 2002a; Van der Pal 2005). Many studies have been performed on cardioprotective strategies, such as infusion duration (Van Dalen 2009), different anthracycline derivates (Van Dalen 2010) and cardioprotective agents like dexrazoxane (Van Dalen 2011a; Van Dalen 2011b). However CHF remains a problem.

Why it is important to do this review

It is important to gain more insight into the incidence and associated risk factors of anthracycline- and irradiation-associated CHF. Due to the increase in survival of patients treated for childhood, adolescent and young adult cancer, more people are at risk of developing this serious cardiac adverse event. At the moment no adequate treatment is available for anthracycline-associated HF (Sieswerda 2011), and treatment for radiation-associated CHF is limited (Handa 2000). The occurrence of anthracycline- and irradiation-associated CHF has an immediate effect on the quality of life of children, adolescents and young adults treated with anthracyclines and/or irradiation involving the heart region, and on medical costs in general. Furthermore, physicians developing new treatment and screening protocols should take CHF into account.

Objectives

To evaluate the existing evidence for an association between childhood, adolescent and young adult cancer treatment with anthracyclines and/or irradiation involving the heart region and the occurrence of both early and late clinical heart failure (CHF).

Methods

Criteria for considering studies for this review

Types of studies

All study designs, except for case reports, case series (i.e., a description of non-consecutive patients) and studies including fewer than 100 patients, treated with potentially cardiotoxic therapy, examining the association between childhood, adolescent and young adult cancer treatment including anthracyclines and/or irradiation involving the heart region, and the occurrence of clinical heart failure (CHF), or death due to CHF or heart transplant after CHF. We defined cohort studies as those in which a group of consecutive patients was followed from a similar well-defined point in the course of the disease. The described study group could be the original cohort or a subgroup of the original cohort, based on well-defined inclusion criteria.

Types of participants

Children, adolescents and young adults treated with anthracyclines (doxorubicin, daunorubicin, epirubicin and/or idarubicin) and/or irradiation involving the heart region, aged between 0 and 25 years at the time of the cancer diagnosis. Studies that included both children and adults are only eligible for inclusion if the majority of the participants were children, adolescents or young adults aged 25 or less at cancer diagnosis (i.e, either more than 90% were between 0 and 25 year, or the maximum age did not exceed 30 years); or if the study presents results for children, adolescents and/or young adult cancer patients separately.

Types of interventions

Treatment with anthracyclines (doxorubicin, daunorubicin, epirubicin and/or idarubicin) and/or irradiation involving the heart region (i.e., total body irradiation, left or whole abdominal irradiation, spinal irradiation and thoracic irradiation), given as treatment for a primary childhood, adolescent or young adult cancer. Studies which also include some patients who did not receive anthracyclines and/or irradiation involving the heart are only eligible for inclusion if separate data are available for those patients treated with anthracyclines and/or irradiation involving the heart.

Types of outcome measures

  • Anthracycline- and/or irradiation-associated CHF (symptoms, NYHA II, III and IV (http://www.escardio.org/guidelines-surveys/esc-guidelines/Pages/acute-chronic-heart-failure.aspx), CTCAE3.0 grade 3 and 4 or CTCAE4.0 grade 2, 3 and 4 (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm)

  • Heart transplant because of anthracycline- and/or irradiation-associated CHF

  • Death due to anthracycline- and/or irradiation-associated CHF (i.e., CTCAE3.0 or CTCAE4.0 grade 5)

Search methods for identification of studies

See: Cochrane Childhood Cancer Group methods used in reviews (Module CCG).

We will not impose any language restrictions.

We will update the searches every two years.

Electronic searches

We will search the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue), MEDLINE/PubMed (from 1945 to present), and EMBASE/Ovid (from 1980 to present).

The search strategies for the different electronic databases (using a combination of controlled vocabulary and text words) are shown in the appendices (Appendix 1; Appendix 2; Appendix 3).

Searching other resources

We will locate information about trials not registered in CENTRAL, PubMed/MEDLINE or EMBASE, either published or unpublished, by searching the reference lists of relevant articles and review articles. We will handsearch the conference proceedings of the International Society for Paediatric Oncology (SIOP), American Society of Clinical Oncology (ASCO), American Society of Pediatric Hematology/Oncology (ASPHO), European Symposium on Late Complications after Childhood Cancer (ESLCCC), and International Conference on Long-Term Complications of Treatment of Children and Adolescents for Cancer (last five years in all cases). Appendix 4 describes how these searches will be performed for the first four sets of conference proceedings. The International Conference on Long-Term Complications of Treatment of Children and Adolescents for Cancer will be searched on paper.

Data collection and analysis

Selection of studies

After performing the searches as described above, two authors will independently select appropriate articles; if they can not agree, a third author will act as arbiter. We will obtain full reports of any study which seems to meet the inclusion criteria on the grounds of the title or abstract, or both, for closer inspection. We will use the full study report to check if it meets all the inclusion criteria. We will collect and report all reasons for any exclusion will be collected and displayed. We will calculate a kappa statistic to assess interobserver agreement. When articles are using data from the same study population, established by comparison of authors, location and cohort specifications (name cohort, year start and end, etc.) we will include a single report in the review, preferably the one covering most included patients or most recent data.

Data extraction and management

Two reviewers will independently perform data extraction, using standardised forms. We will extract data on the following items:

1. Study characteristics:

  • Study design

  • Number of patients in the original cohort

  • Number of patients in the described study group

  • Number of patients with an outcome measure

2. Participant features:

  • Age at diagnosis

  • Age at follow-up

  • Gender

  • Malignancy

  • Follow-up

  • Subgroups (if the study assessed those)

3. Interventions:

  • Number of patients who received anthracyclines

  • Number of patients who received Irradiation involving the heart region.

  • Number of patients who received both anthracyclines and irradiation involving the heart region

  • Type of anthracycline

  • Cumulative dose of anthracycline

  • Cumulative weekly dose of anthracycline (as mentioned by the authors)

  • Infusion duration of anthracycline

  • Cumulative dose of irradiation involving the heart region

4. Outcomes:

  • Outcome definitions

  • Method of detection

  • Time point(s) at which outcome data were collected

5. Results:

  • Incidence of clinical heart failure (CHF)

  • Incidence of transplant due to CHF

  • Incidence of death due to CHF

  • Subgroup analyses (e.g., different therapy received, gender, age at cancer diagnosis, duration of follow-up)

6. Risk factors

7. Length of follow-up

In case 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 by using a third author to act as arbiter.

Assessment of risk of bias in included studies

Two authors will independently undertake the assessment of risk of bias of the included studies. For randomised controlled trials (RCTs) and controlled clinical trials (CCTs), we will use the risk of bias items as described in the module of the Childhood Cancer Group (Module CCG), which are based on the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).The assessment of risk of bias in observational studies will be based on earlier described checklists for observational studies according to Evidence-Based Medicine Criteria (Grimes 2002; Laupacis 1994). The risk of bias assessment criteria for observational studies are described in Table 1. For the risk of bias assessment of case-control studies, the criteria will be slightly adapted for the selection of cases and controls, which should be based on comparable patient characteristics (e.g., age at cancer diagnosis, gender, length of follow-up and cancer treatment). If the two authors can not agree, a third author will act as arbiter. The risk of bias in included studies will be taken into account in the interpretation of the review's results.

Table 1. Risk of bias assessment criteria for observational studies
 Internal validityExternal validity
Study groupSelection bias (representative: yes/no)
• if the described study group consisted of more than 95% of the original cohort of children, adolescents and young adults treated with anthracyclines and/or irradiation involving the heart region
• or if it was a random sample with respect to the cancer treatment
Reporting bias (well-defined: yes/no)
• if the mean, the median or the range of the cumulative anthracycline and irradiation dose, other potential cardiotoxic treatment (mitoxantrone, ifosfamide, cyclophosphamide and vincristine) was mentioned and prior cancer treatment (++).
• if only the mean, the median or the range of the cumulative anthracycline and irradiation dose was mentioned (+)
Follow-upAttrition bias (adequate: yes/no)
• if the outcome was assessed for more than 95% of the study group of interest (++)
• or if the outcome was assessed for 65-95% of the study group of interest (+)
Reporting bias (well-defined: yes/no)
• if the length of follow-up was mentioned
OutcomeDetection bias (blind: yes/no)
• if the outcome assessors were blinded to the investigated determinant
Reporting bias (well-defined: yes/no)
• if the outcome definition was objective and precise; according to symptoms, NYHA and/ or CTCAEv3.0 or CTCAEv4.0
Risk estimationConfounding (adjustment for other factors: yes/no)
• if important prognostic factors (i.e., age, gender, co-treatment) or follow-up were taken adequately into account
Analyses (well-defined: yes/no)
• if a risk ratio, odds ratio, attributable risk, linear or logistic regression model, mean difference or Chi² was calculated

Measures of treatment effect

Prevalence, cumulative incidence, mean difference, absolute and relative risk, odds ratio, attributable risk, and other associated outcomes.

Dealing with missing data

When relevant data regarding study selection, data extraction and risk of bias assessment are missing, we will attempt to contact the study authors to retrieve the missing information.

Assessment of heterogeneity

We will assess heterogeneity both by visual inspection of the forest plots and by a formal statistical test for heterogeneity, i.e., the I² statistic. If significant heterogeneity (I² > 50%) (Higgins 2011) is identified, we will explore possible reasons and take appropriate measures.

Assessment of reporting biases

In addition to the evaluation of reporting bias as described in the 'Assessment of risk of bias' section, we will assess it by constructing a funnel plot, provided there are a sufficient number of included studies (i.e., at least 10 studies included in a meta-analysis). When there are fewer studies the power of the tests is too low to distinguish chance variation from real asymmetry (Higgins 2011).

Data synthesis

We will use a random-effects model for the pooling of treatment effects. Where pooling of studies is not possible, we will summarise studies descriptively. We will present all results with the corresponding 95% confidence interval. We will conduct all analyses according to the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), and with the statistical components of Review Manager 5.1. We will include outcome measures only if it was the intention of the study to perform the necessary assessments in all included patients (i.e., not an optional outcome or only performed in some centres). When the results of a particular outcome measure are available for fewer than 50% of the patients in a study, we will not report the results of this outcome measure, which may be at high risk of attrition bias. We will pool results only if studies (observational studies) or treatment groups (RCTs and CCTs) are comparable, including the outcome definitions that were used. Different study designs will be taken into account in the analyses. We will summarise risk factors descriptively, and only those studies which performed a multivariate analysis (i.e., including two or more potential predictive factors) will be included; case-control studies are also eligible.

Sensitivity analysis

For all outcomes for which pooling is possible, we will perform sensitivity analyses for all risk of bias criteria separately. We will exclude studies with a high or an unclear risk of bias, and compare the results of studies with a low risk of bias with those of all available studies.

Acknowledgements

Leontien Kremer and Elvira van Dalen, the Co-ordinating Editors of the Childhood Cancer Group, are co-authors of this review and therefore could not act as the Editors of this review. Renée Mulder (Department of Paediatric Oncology of the Emma Children's Hospital/Academic Medical Center, Amsterdam, the Netherlands) was willing to take on this task, for which we would like to thank her. The editorial base of the Cochrane Childhood Cancer Group is funded by Stichting Kinderen Kankervrij (KiKa).

We also thank Dr D. Mulrooney (St. Jude Children's Research Hospital, Memphis, USA), Dr E. Vandencruys (Department of Pediatric Hemato-Oncology, Gent University Hospital, Gent, Belgium) and Prof J. Steinberger (Department of Pediatrics, University of Minnesota Medical Center, Minneapolis, USA.) who kindly agreed to peer review our manuscript.

Appendices

Appendix 1. Search strategy for Cochrane Central Register of Controlled Trials (CENTRAL)

1.For Anthracyclines the following text words will be used:

anthracyclines OR anthracyclin* OR anthracycline antibiotics OR 4-demethoxydaunorubicin OR 4 demethoxydaunorubicin OR 4-desmethoxydaunorubicin OR 4 desmethoxydaunorubicin OR IMI 30 OR IMI30 OR IMI-30 OR idarubicin hydrochloride OR NSC 256439 OR NSC-256439 OR NSC256439 OR idarubicin OR idarubic* OR 4'-epiadriamycin OR 4' epiadriamycin OR 4'-epidoxorubicin OR 4' epidoxorubicin OR 4'-epi-doxorubicin OR 4' epi doxorubicin OR 4'-epi-adriamycin OR 4' epi adriamycin OR 4'-epi-DXR OR 4' epi DXR OR epirubicin hydrochloride OR farmorubicin OR IMI-28 OR IMI 28 OR IMI28 OR NSC 256942 OR NSC-256942 OR NSC256942 OR epirubicin OR epirubic* OR adriablastine OR adriblastin OR adriablastin OR adriamycin OR DOX-SL OR DOX SL OR doxorubicin hydrochloride OR doxorubic* OR adriamyc* OR dauno-rubidomycine OR dauno rubidomycin OR rubidomycin OR rubomycin OR daunomycin OR cerubidine OR daunoblastin OR daunoblastine OR daunorubicin hydrochloride OR hydrochloride, daunorubicin OR daunorubic* OR rubidomyc* OR NSC-82151 OR NSC 82151 OR NSC82151 OR daunoxome OR daunoxom* OR daunosom* OR doxil OR caelyx OR liposomal doxorubicin OR myocet OR doxorubicin OR daunorubicin

2. For Irradiation the following text words will be used:

radiation OR radiation injuries OR radiation induced OR radiotherapy OR radiotherapies OR radiotherap* OR irradiation OR chest wall radiotherapy OR thoracic radiotherapy OR thorax radiation OR chest radiation OR radiotherapy heart OR heart irradiation OR lymph node radiotherapy OR lymph node irradiation OR Involved-Node Radiotherapy OR mediastinal irradiation OR radiation dose

3. For Clinical heart failure the following text words will be used:

Congestive heart failure OR CHF OR heart failure OR clinical heart failure OR clinical cardiotoxicity OR clinical cardiotoxicities OR clinical cardiotoxicit* OR Cardiac Failure OR Myocardial Failure OR Left-Sided Heart Failure OR Left Sided Heart Failure OR Right-Sided Heart Failure OR Right Sided Heart Failure OR Heart Failure, Congestive OR Heart Decompensation OR cardiomyopathy OR cardiomyopathies OR cardiomyopath* OR cardiac damage OR cardiac toxicity OR cardiac toxicities OR cardiac dysfunction OR cardiac dysfunctions OR cardiac failure OR cardiac failures OR heart pathology OR heart disease OR heart diseases

4. For Children the following text words will be used:

infan* OR newborn* OR new-born* OR perinat* OR neonat* OR baby OR baby* OR babies OR toddler* OR minors OR minors* OR boy OR boys OR boyfriend OR boyhood OR girl* OR kid OR kids OR child OR child* OR children* OR schoolchild* OR schoolchild OR school child OR school child* OR adolescen* OR juvenil* OR youth* OR teen* OR under*age* OR pubescen* OR pediatrics OR pediatric* OR paediatric* OR peadiatric* OR school OR school* OR prematur* OR preterm* OR young adult OR young adults OR young women OR young men OR young male OR young female

Final search (1 OR 2) and 3 and 4

The search will be performed in title, abstract or keywords

[*= zero or more characters]

Appendix 2. Search strategy for Medline/PubMed

1. For Anthracyclines the following MeSH headings and text words will be used:

anthracyclines OR anthracyclin* OR anthracycline antibiotics OR antibiotics, anthracycline OR 4-demethoxydaunorubicin OR 4 demethoxydaunorubicin OR 4-desmethoxydaunorubicin OR 4 desmethoxydaunorubicin OR IMI 30 OR IMI30 OR IMI-30 OR idarubicin hydrochloride OR hydrochloride, idarubicin OR NSC 256439 OR NSC-256439 OR NSC256439 OR idarubicin OR idarubic* OR 4'-epiadriamycin OR 4' epiadriamycin OR 4'-epidoxorubicin OR 4' epidoxorubicin OR 4'-epi-doxorubicin OR 4' epi doxorubicin OR 4'-epi-adriamycin OR 4' epi adriamycin OR 4'-epi-DXR OR 4' epi DXR OR epirubicin hydrochloride OR hydrochloride, epirubicin OR farmorubicin OR IMI-28 OR IMI 28 OR IMI28 OR NSC 256942 OR NSC-256942 OR NSC256942 OR epirubicin OR epirubic* OR adriablastine OR adriblastin OR adriablastin OR adriamycin OR DOX-SL OR DOX SL OR doxorubicin hydrochloride OR hydrochloride, doxorubicin OR doxorubic* OR adriamyc* OR dauno-rubidomycine OR dauno rubidomycin OR rubidomycin OR rubomycin OR daunomycin OR cerubidine OR daunoblastin OR daunoblastine OR daunorubicin hydrochloride OR hydrochloride, daunorubicin OR daunorubic* OR rubidomyc* OR NSC-82151 OR NSC 82151 OR NSC82151 OR daunoxome OR daunoxom* OR daunosom* OR doxil OR caelyx OR liposomal doxorubicin OR doxorubicin, liposomal OR myocet OR doxorubicin OR daunorubicin

2. For Irradiation the following MeSH headings and text words will be used:

radiation OR radiation injuries OR radiation induced OR radiotherapy OR radiotherapies OR radiotherap* OR radiotherapy[sh] OR radiotherapy/adverse effects OR irradiation OR radiation effects[sh] OR chest wall radiotherapy OR thoracic radiotherapy OR thorax radiation OR chest radiation OR radiotherapy heart OR heart irradiation OR lymph node radiotherapy OR lymph node irradiation OR Involved-Node Radiotherapy OR mediastinal irradiation OR radiation dose

3. For Clinical heart failure the following MeSH headings and text words will be used:

Congestive heart failure OR CHF OR heart failure OR clinical heart failure OR clinical cardiotoxicity OR clinical cardiotoxicities OR clinical cardiotoxicit* OR Cardiac Failure OR Myocardial Failure OR Heart Failure, Left-Sided OR Heart Failure, Left Sided OR Left-Sided Heart Failure OR Left Sided Heart Failure OR Heart Failure, Right-Sided OR Heart Failure, Right Sided OR Right-Sided Heart Failure OR Right Sided Heart Failure OR Heart Failure, Congestive OR Heart Decompensation OR Decompensation, Heart OR cardiomyopathy OR cardiomyopathies OR cardiomyopath* OR cardiac damage OR cardiac toxicity OR cardiac toxicities OR cardiac dysfunction OR cardiac dysfunctions OR cardiac failure OR cardiac failures OR heart pathology OR heart/radiation effects OR heart ventricles/radiation effects OR heart disease OR heart diseases

4. For Children the following MeSH headings and text words will be used:

infan* OR newborn* OR new-born* OR perinat* OR neonat* OR baby OR baby* OR babies OR toddler* OR minors OR minors* OR boy OR boys OR boyfriend OR boyhood OR girl* OR kid OR kids OR child OR child* OR children* OR schoolchild* OR schoolchild OR school child[tiab] OR school child*[tiab] OR adolescen* OR juvenil* OR youth* OR teen* OR under*age* OR pubescen* OR pediatrics[mh] OR pediatric* OR paediatric* OR peadiatric* OR school[tiab] OR school*[tiab] OR prematur* OR preterm* OR young adult OR young adults OR young women[tiab] OR young men[tiab] OR young male[tiab] OR young female[tiab]

5. For Case reports the following MeSH headings and text words will be used:

case reports OR case report

Final search ((1 OR 2) and 3 and 4) NOT 5

{*= zero or more characters; tiab=title or abstract; sh=subject heading; mh=MeSH term]

Appendix 3. Search strategy for EMBASE/OVID

1. For Anthracyclines the following Emtree terms and text words will be used:

1. (anthracyclin$ or anthracyclines).mp. or exp Anthracycline/
2. anthracycline antibiotics.mp. or exp Anthracycline Antibiotic Agent/
3. exp Anthracycline Derivative/
4. (4-demethoxydaunorubicin or 4 demethoxydaunorubicin or 4-desmethoxydaunorubicin or 4 desmethoxydaunorubicin).mp. or exp idarubicin/ [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]
5. (IMI 30 or IMI30 or IMI-30 or idarubicin hydrochloride).mp.
6. (NSC 256439 or NSC-256439 or NSC256349 or idarubicin or idarubic$).mp.
7. (4'-epiadriamycin or 4' epiadriamycin or 4'-epidoxorubicin or 4' epidoxorubicin or 4'-epi-doxorubicin or 4' epi doxorubicin).mp.
8. (4'-epi-adriamycin or 4' epi adriamycin or 4'-epi-DXR or 4' epi DXR).mp.
9. exp epirubicin/ or (epirubicin or epirubicin hydrochloride or epirubic$ or farmorubicin).mp.
10. (IMI-28 or IMI 28 or IMI28 or NSC 256942 or NSC-256942 or NSC256942).mp.
11. (adriablastine or adriblastin or adriablastin or adriamycin).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]
12. (DOX-SL or DOX SL or doxorubicin hydrochloride or doxorubic$ or adramyc$).mp.
13. (dauno-rubidomycine or dauno rubidomycin or rubidomycin or rubomycin or daunomycin).mp.
14. (cerubidine or daunoblastin or daunoblastine or daunorubicin hydrochloride or daunorubic$).mp.
15. (NSC-82151 or NSC 82151 or NSC82151).mp.
16. (daunoxome or daunoxom$ or daunosom$ or doxil or caelyx or liposomal doxorubicin or myocet or doxorubicin or daunorubicin).mp.
17. exp DAUNORUBICIN DERIVATIVE/ or exp DAUNORUBICIN/ or exp IDARUBICIN DERIVATIVE/ or exp IDARUBICIN/ or exp DOXORUBICIN DERIVATIVE/ or exp DOXORUBICIN/ or exp EPIRUBICIN/
18. or/1-17

2. For Irradiation the following Emtree terms and text words will be used:

1. radiation.mp. or exp radiation/
2. radiation injuries.mp. or exp radiation injury/
3. radiation induced.mp.
4. exp radiotherapy/
5. (radiotherapy or radiotherapies or radiotherap$).mp.
6. radiotherapy.sh.
7. irradiation.mp. or exp irradiation/
8. (radiation dose distribution or radiation induced heart disease or radiation induced cardiomyopathy or radiation induced cardiotoxicity or radiation induced
cardiovascular disease).sh.
9. chest wall radiotherapy.mp.
10. thoracic radiotherapy.mp.
11. thorax radiation.mp.
12. chest radiation.mp.
13. radiotherapy heart.mp.
14. heart radiotherapy.mp.
15. heart irradiation.mp.
16. lymph node radiotherapy.mp. or exp lymph node irradiation/
17. lymph node irradiation.mp.
18. involved-node radiotherapy.mp.
19. mediastinal irradiation.mp.
20. radiation dose.mp. or exp radiation dose/
21. or/1-20

3. For Clinical heart failure the following Emtree terms and text words will be used:

1. exp congestive heart failure/
2. (congestive heart failure or CHF).mp.
3. heart failure.mp. or exp heart failure/
4. clinical heart failure.mp.
5. (clinical cardiotoxcity or clinical cardiotoxicities or clinical cardiotoxicit$).mp.
6. cardiac failure.mp. or exp heart failure/
7. Myocardial Failure.mp.
8. left sided heart failure.mp.
9. right sided heart failure.mp.
10. heart decompensation.mp.
11. exp cardiomyopathy/
12. (cardiomyopathy or cardiomyopathies or cardiomyopath$).mp.
13. cardiac damage.mp.
14. exp cardiotoxicity/
15. (cardiac toxicity or cardiac toxicities).mp.
16. (cardiac dysfunction or cardiac dysfunctions).mp.
17. (cardiac failure or cardiac failures).mp.
18. heart pathology.mp.
19. exp heart disease/
20. (heart disease or heart diseases).mp.
21. or/1-20

4. For Children the following Emtree terms and text words will be used:

1. infan$.mp.
2. (newborn$ or new-born$).mp.
3. (perinat$ or neonat$).mp.
4. baby/
5. (baby or baby$ or babies).mp.
6. toddler$.mp.
7. (minors or minors$).mp.
8. (boy or boys or boyfriend or boyhood).mp.
9. girl$.mp.
10. (kid or kids).mp.
11. child/
12. (child or child$ or children$).mp.
13. school child/
14. (schoolchild$ or schoolchild).mp.
15. (school child or school child$).ti,ab.
16. (adolescen$ or youth$ or teen$).mp.
17. (juvenil$ or under$age$).mp.
18. pubescen$.mp.
19. exp pediatrics/
20. (pediatric$ or paediatric$ or peadiatric$).mp.
21. (school or school$).mp.
22. (prematur$ or preterm$).mp.
23. (young adult or young adults or young adult$).mp.
24.(young women or young men or young male or young female).mp.
25. or/1-24

5. For Case reports the following Emtree terms and text words will be used:

1. case reports or case report

Final search ((1 or 2) and 3 and 4) not 5

[mp = title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name; sh = subject heading; ti,ab = title or abstract; / = Emtree term; $= zero to many characters]

Appendix 4. Search strategies for proceedings abstracts and trial registers

The pdf files of SIOP and ESLCCC abstracts will be searched for "cardiotox" and for "heart failure". The ASCO abstracts will be searched for "cardiotoxicity" and for "heart failure" in the abstract (http://www.asco.org/ASCOv2/Meetings/Abstracts). The ASPHO abstracts will be searched for "cardiotoxicity" and for "heart failure" in the abstract.

Declarations of interest

None known

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Stichting Kinder Kankervrij (KiKa), Not specified.

Ancillary