P9404.

Study characteristics
Methods	Method of randomisation not clear (stratified by disease (T‐ALL versus NHL) and presence of CNS disease at diagnosis).
Participants	537 children (mean age 9.8 years; 407 males and 130 females) with T‐ALL (N = 362; stage unclear) or L‐NHL (N = 174; stage III or IV) (for 1 participant the diagnosis was nm) treated with doxorubicin (cumulative dose nm, but according to protocol all participants should have received 360 mg/m2 and it was reported that all participants received the same cumulative dose; peak dose (i.e. maximal dose received in 1 week) nm; infusion duration nm), vincristine, prednisone, methotrexate (some participants), mercaptopurine, Escherichia coli L‐asparaginase, intrathecal chemotherapy and cranial radiation). Prior anthracyclines no. Prior cardiac radiotherapy possible (emergency mediastinal radiotherapy for severe respiratory distress was allowed), but numbers nm. Prior cardiac dysfunction nm.
Interventions	Dexrazoxane (300 mg/m2 in 10:1 ratio of dexrazoxane to doxorubicin; IV bolus infusion immediately before each doxorubicin dose; exact infusion duration nm) (n = 273) versus no cardioprotective intervention (n = 264).
Outcomes	Heart failure (i.e. clinical heart failure (no definition provided); primary cause of death cardiomyopathy/heart failure; subclinical myocardial dysfunction defined as decreased LVFS; however it was stated that toxicity was graded according to NCI CTCAEv2 criteria, grade 3 or higher but LVFS is not included in that definition) Overall mortality (time from cancer diagnosis to death) Adverse effects (according to NCI CTCAEv2)
Notes	Length of follow‐up: median 9.2 years (range 0.01 to 15.0) (in intervention group 9.4 years (0.01 to 15) and in control group 8.9 years (0.02 to 14.7)) Mean age in intervention group 9.9 years and in control group 9.7 years Cumulative anthracycline dose per treatment group nm, but it was reported that all participants received the same cumulative dose. Gender: 69 (25.3%) females and 204 (74.7%) males in the dexrazoxane group and 61 (23.1%) females and 203 (76.9%) males in control group. Stage of disease per treatment group: for T‐ALL nm. For L‐NHL in intervention group: stage III N = 52 (19%) and stage IV N = 33 (12.1%) and in the control group stage III N = 67 (25.4%) and stage IV N = 22 (8.3%). Long‐term follow‐up data for overall mortality and primary cause of death cardiomyopathy/heart failure have been published, these outcomes were not included in the original publication by P9404 (P9426); all 537 randomised participants were included; median follow‐up was 12.4 years (range 0 to 15.5). Funding sources: supported in part by the Clinical Trials Evaluation Program of the National Cancer Institute, National Institutes of Health grants No. U10 CA098543, U10 CA098413, U10 CA180886, and U10 CA180899, and the Michael Garil Fund. A complete listing of grant support for research conducted by the Pediatric Oncology Group and Children’s Cancer Study Group before initiation of the Children’s Oncology Group grant in 2003 is available online at http://www.childrensoncologygroup.org/admin/grantinfo.htm (P9404) and grants No. U10 CA09543 and K07 CA151775 from the US National Institutes of Health, by St Baldrick’s Foundation, and by the Leukemia and Lymphoma Society for the Children’s Oncology Group study (Effects of Dexrazoxane Hydrochloride on Biomarkers Associated With Cardiomyopathy and Heart Failure After Cancer Treatment [HEART (ALTE11C2)]) (P9426). Declaration of interests: some authors reported research funding by Amgen, MedImmune, Bristol‐Myers Squibb, Becton Dickinson, Pfizer, Roche and consulting or advisory roles and speakers' bureau by Clinigen Group, Jazz Pharmaceuticals, Sigma Tau Pharmaceuticals (P9404) and some authors reported research funding by Merck, Roche Diagnostics, Pfizer and consulting or advisory roles and speakers' bureau by Clinigen Group, Jazz Pharmaceuticals, Sigma Tau Pharmaceuticals and travel, accommodation and expenses by Clinigen Group (P9426). The Asselin 2012 publication was a conference proceeding of this study; we did not use information from this publication. The Fernandez 2017 publication was a duplicate publication of this study, but as no data on dexrazoxane versus control participants was provided we did not use any information from this publication.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	It was stated that this was a randomised study, but no further information on the method of randomisation was provided.
Allocation concealment (selection bias)	Unclear risk	It was stated that this was a randomised study, but no further information on the method of randomisation was provided.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Participants and personnel were not blinded to the received intervention (either dexrazoxane or no cardioprotective intervention).
Blinding of outcome assessors (detection bias) ‐ clinical heart failure	Unclear risk	No information on blinding of outcome assessors provided for clinical heart failure
Blinding of outcome assessors (detection bias) ‐ cardiomyopathy/heart failure as primary cause of death	Low risk	The outcome assessors of cardiomyopathy/heart failure as primary cause of death were blinded to treatment.
Blinding of outcome assessors (detection bias) ‐ clinical heart failure and subclinical myocardial dysfunction combined	Unclear risk	The outcome assessors for subclinical myocardial dysfunction were blinded to the treatment assignment of the participants, but no information on blinding of outcome assessors provided for clinical heart failure
Blinding of outcome assessors (detection bias) ‐ overall survival/overall mortality	Low risk	No information on blinding of outcome assessors provided, but as blinding is not relevant for the outcome overall mortality, we judged this outcome at low risk of detection bias.
Blinding of outcome assessors (detection bias) ‐ toxicities other than cardiac damage (not diagnosed by laboratory tests)	Unclear risk	No information on blinding of outcome assessors provided for toxicities other than cardiac damage (haematologic effects might include toxicities diagnosed by laboratory tests only and thus at a low risk of bias, but as this was not further specified, we judged this outcome to be at unclear risk).
Incomplete outcome data (attrition bias) ‐ clinical heart failure	Low risk	Clinical heart failure evaluated in 100% of participants in both treatment groups.
Incomplete outcome data (attrition bias) ‐ cardiomyopathy/heart failure as primary cause of death	Low risk	Cardiomyopathy/heart failure as primary cause of death evaluated in 100% of participants in both treatment groups.
Incomplete outcome data (attrition bias) ‐ clinical heart failure and subclinical myocardial dysfunction combined	High risk	Clinical heart failure evaluated in 100% of all participants in both treatment groups; for subclinical myocardial dysfunction, an overall number for the actual time point included for each participant in the analyses is missing, but subclinical myocardial dysfunction was evaluated in between 30% (82/273) and 11% (31/273) of participants in the intervention group and between 32% (84/264) and 8% (21/264) in the control group at different time points, so we judged this to be a high risk of bias.
Incomplete outcome data (attrition bias) ‐ overall survival/overall mortality	Low risk	Overall mortality evaluated in 100% of participants in both treatment groups.
Incomplete outcome data (attrition bias) ‐ toxicities other than cardiac damage with the exception of SMN	Low risk	Toxicities other than cardiac damage were evaluated in 100% of participants in both treatment groups.
Incomplete outcome data (attrition bias) ‐ SMN	Low risk	SMN evaluated in 100% of participants in both treatment groups.
Selective reporting (reporting bias)	Low risk	All expected outcomes were reported.
Other bias	Unclear risk	Block randomisation in unblinded trials: unclear (information on both method of randomisation and blinding of some of the outcome assessors not provided). Baseline imbalance between treatment groups related to outcome (prior cardiotoxic treatment (anthracyclines and cardiac irradiation), age, gender, stage of disease and prior cardiac dysfunction): unclear for prior cardiac radiotherapy, stage of disease and prior cardiac dysfunction; other items no imbalance Difference in length of follow‐up between treatment groups: comparable between treatment groups