P9426.

Study characteristics
Methods	Method of randomisation not clear.
Participants	255 children (median age 14 years (range 2.1 to 20.9); 150 males and 105 females) with low risk HL (N = 61 stage IA, N = 179 IIA, N = 14 IIIA1 and N = 1 nm)treated with doxorubicin (cumulative dose nm, but according to study protocol this ranged from 100 to 200 mg/m2 and it was stated that received dose was in high compliance with prescribed dose); peak dose (i.e. maximal dose received in 1 week) 25mg/m2; infusion duration: push), vincristine, bleomycin, and etoposide followed, at least for some children, by involved region consolidative radiotherapy. Prior anthracyclines no. Prior cardiac radiotherapy no. Prior cardiac dysfunction nm.
Interventions	Dexrazoxane (250 mg/m2 in 10:1 ratio of dexrazoxane to doxorubicin; IV bolus/push infusion maximal 30 minutes before each doxorubicin dose (see notes)) (N = 127) versus no cardioprotective intervention (N = 128).
Outcomes	Heart failure (i.e. primary cause of death cardiomyopathy/heart failure) Overall mortality (time from cancer diagnosis to death) Adverse effects (definition nm).
Notes	Length of follow‐up: median 12.4 years (range 1.4 to 15) (in intervention group 12.4 years (1.4 to 15) and in control group 12.4 years (1.8 to 14.8)). Median age at treatment in intervention group 14.2 years (range 2.1 to 20.9) and in control group 13.9 years (3.7 to 19.7). Cumulative anthracycline dose per treatment group nm. Gender: 53 (41.7%) females and 74 (58.3%) males in the dexrazoxane group and 52 (40.6%) females and 76 (59.4%) males in control group. Stage of disease per treatment group: all low risk. Data for secondary malignancies have been published (Tebbi 2007); 262 randomised participants were included (seven more than in P9426 primary reference); median follow‐up was 55.5 months from date of enrolment. Gender 153 males and 109 females; median age at diagnosis 12.5 years. It was stated that dexrazoxane was also given prior to bleomycin. Data for adverse effects other than secondary malignancies have been published (Tebbi 2012); all 255 randomised participants were included; median follow‐up time 7.5 years in participants alive without an event. Age was reported as median 13 years (range 2 to 20); unclear if this is age at diagnosis or age at treatment and therefore unclear if different from P9426 primary reference. It was stated that dexrazoxane was also given prior to bleomycin. Funding sources: supported by 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 primary reference); not reported (Tebbi 2007); QARC GRANT NIH/NCI CA29511, the Chair’s Grant U10 CA98543‐08 and Statistics and Data Center Grant U10 CA98413‐08 of the Children’s Oncology Group from the National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. A complete listing of grant support for research conducted by CCG and POG before initiation of the COG grant in 2003 is available online at: http://www.childrensoncologygroup.org/admin/grantinfo.htm (Tebbi 2012). Declaration of interests: some authors reported research funding by Merck, Roche Diagnostics, Pfizer and consulting or advisory roles and speakers' bureau by Clinigen Group, Jazz Pharmaceuticals, Sima Tau Pharmaceuticals and travel, accommodation and expenses by Clinigen Group (P9426 primary reference); nothing to declare (Tebbi 2007; Tebbi 2012). The Chow 2014 publication is a conference proceeding of this study; we did not use 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) ‐ 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) ‐ overall survival/overall mortality	Low risk	The outcome assessors of overall mortality were blinded to treatment.
Blinding of outcome assessors (detection bias) ‐ toxicities other than cardiac damage (diagnosed by laboratory tests)	Low risk	No information on blinding of outcome assessors provided, but as blinding is not relevant for outcomes diagnosed by laboratory test, we judged this outcome at low risk of detection bias for the following adverse effects: white blood cell count, absolute neutrophil count, lymphs, platelets and haemoglobin.
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 not diagnosed by a laboratory test (i.e. all toxicities not mentioned above).
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) ‐ 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	High risk	Toxicities other than cardiac damage evaluated in 86% of participants in the dexrazoxane group and 88% in the control group (109/127 of the dexrazoxane group and 113/128 of the control group).
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 stage of disease and prior cardiac dysfunction; other items no imbalance Difference in length of follow‐up between treatment groups: comparable between treatment groups for P9426 primary reference; for Tebbi 2007 and Tebbi 2012 nm.