P9425.

Study characteristics
Methods	Method of randomisation not clear.
Participants	216 children (mean age 14 years (range 4 to 21); 140 males and 76 females) with intermediate or high risk Hodgkin lymphoma (stage IB N = 1, stage II N = 81, stage III N = 52, stage IV N = 70, stage unknown N = 12) treated with multiagent chemotherapy including doxorubicin (cumulative dose nm (according to protocol 180 mg/m2 for participants with rapid early response and 300 mg/m2 for participants with slow early response; it was stated that there were virtually no dose reductions); peak dose (i.e. maximal dose received in 1 week) 60 mg/m2; infusion duration nm). Participants received 21 Gy of radiotherapy to mantle if it involved Hodgkin lymphoma; pericardial infusions, lung disease or pericardial involvement were treated with 10.5 Gy (no further information provided). Prior anthracycline therapy nm. Prior cardiac radiotherapy nm. Prior cardiac dysfunction nm (definition 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 = 107) versus no cardioprotective intervention (N = 109).
Outcomes	Heart failure (i.e. clinical heart failure defined according to NCI‐CTCv2.0 criteria; primary cause of death cardiomyopathy/heart failure) Overall mortality (time from cancer diagnosis to death) Tumour response rate (complete response defined as disappearance of active Hodgkin lymphoma (gallium negative, ≥ 70% decrease in the sum of the products of the perpendicular diameters of measurable lesions, and negative bone marrow or bone scan if initially positive). Adverse effects (according to NCI‐CTCv2.0 criteria).
Notes	Length of follow‐up nm (median follow‐up for participants without an event was 5.2 years). Median age in dexrazoxane group 14.8 years (range 3.7 to 20) and in control group 14.9 years (range 5.6 to 20.8). Cumulative anthracycline dose per treatment group nm. No significant difference in number of participants with rapid and slow early response between treatment groups identified (P = 0.07). It was stated that dexrazoxane was also given on day 7 (besides on day 0 and 1 together with doxorubicin) (in P9426 this was reported to be day 8 in the same 10:1 ratio). Gender: 37 (34.6%) females and 70 (65.4%) males in the dexrazoxane group and 39 (35.8%) females and 70 (64.2%) males in control group. Stage of disease per treatment group: nm. 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 P9425 (P9426); all 216 randomised participants were included; median follow‐up was 13 years (range 0 to 14.7). Funding sources: the Chair’s Grant U10 CA98543 and the Statistics and Data Center (Grant U10 CA98413) of the Children’s Oncology Group (COG) from the National Cancer Institute, National Institutes of Health, Bethesda, MD. 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 (P9425) 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: the authors declare no competing financial interests (P9425) 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). Results on secondary malignant neoplasms were also described in the Tebbi 2007 publication, but as more extended data were available in the other publications we did not use data from the Tebbi 2007 paper.
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) ‐ 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) ‐ tumour response rate	Unclear risk	No information on blinding of outcome assessors provided for tumour response.
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: anaemia, absolute neutrophil count, platelets.
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) ‐ clinical heart failure	Low risk	Clinical heart failure evaluated in 99% of participants in both treatment groups (106/107 of the dexrazoxane group and 108/109 of the control group).
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) ‐ tumour response rate	Low risk	Tumour response evaluated in 94% (101/107) of the dexrazoxane group and 91% (99/109) of the control group.
Incomplete outcome data (attrition bias) ‐ toxicities other than cardiac damage with the exception of SMN	Low risk	Toxicities other than cardiac damage evaluated in 99% of participants in both treatment groups (106/107 of the dexrazoxane group and 108/109 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 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 (similar for age and gender, all other factors unclear) Difference in length of follow‐up between treatment groups: unclear (length of follow‐up nm)