Speyer 1992.

Study characteristics
Methods	Method of randomisation not clear (participants were stratified by prior adjuvant cyclophosphamide, methotrexate and 5FU and cardiac risk factors; blocks of 10 participants within each stratum).
Participants	150 participants (aged 27 to 76 years; all females) with breast cancer (stage nm) treated with doxorubicin (cumulative dose range 25 to 2150 mg/m2; peak dose (i.e. maximal dose received in 1 week) 50 mg/m2; infusion duration 5 to 10 minutes), 5FU and cyclophosphamide. No prior anthracycline therapy. Prior cardiac radiotherapy possible in 28 participants (14 in each treatment group). No prior cardiac dysfunction (defined as congestive heart failure; LVEF on resting MUGA scan < 0.50).
Interventions	Dexrazoxane (20:1 ratio of dexrazoxane to doxorubicin; IV infusion over 15 minutes 30 minutes before doxorubicin) (N = 76) versus no cardioprotective intervention (N = 74).
Outcomes	Heart failure (i.e. clinical heart failure defined as NYHA class 2,3 or 4 i.e. any signs and symptoms of clinical congestive heart failure; subclinical myocardial dysfunction defined as NYHA class 1 i.e. a decrease in LVEF as measured by MUGA of ≥ 20% from baseline or a decrease in LVEF as measured by MUGA to < 45% or an endomyocardial biopsy score ≥ 2 according to the Billingham scale (Billingham 1978)). Tumour response rate (according to ECOG criteria) Overall survival (defined as time to survival; starting point nm) Progression‐free survival (defined as time to progression; starting point nm) Adverse effects (definitions provided, but not according to specific criteria)
Notes	An endomyocardial biopsy was not performed in all participants. Length of follow‐up nm. Age in intervention group: mean 55.5 years and median 58 years; age in control group: mean 56.2 years and median 58 years. Cumulative anthracycline dose in intervention group: mean 558 mg/m2 (range 50 to 2150); cumulative anthracycline dose in control group: mean 407.4 mg/m2 (range 25 to 950). Gender: all females in both treatment groups. Stage of disease per treatment group nm. Funding sources: grant no. 36524 from the United States Public Health Service, by grants no. CA‐16087 and CRC‐RR‐99 from the National Institutes of Health, by the Lila Motley Foundation, and by the Chemotherapy Foundation. Dexrazoxane was supplied by the NCI. Declaration of interests nm. The Speyer 1988 and Speyer 1990 publications are duplicate publications of this study; we did not use information from these publications.
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	Low risk	The outcome assessors of clinical heart failure were blinded to treatment.
Blinding of outcome assessors (detection bias) ‐ clinical heart failure and subclinical myocardial dysfunction combined	Low risk	The outcome assessors of both clinical heart failure and subclinical cardiac damage 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 survival, 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) ‐ progression‐free survival	Unclear risk	No information on blinding of outcome assessors provided for PFS
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
Incomplete outcome data (attrition bias) ‐ clinical heart failure	Low risk	Clinical heart failure evaluated in 100% of all participants in both treatment groups.
Incomplete outcome data (attrition bias) ‐ clinical heart failure and subclinical myocardial dysfunction combined	Unclear risk	Clinical heart failure evaluated in 100% of all participants in both treatment groups; unclear in how many participants subclinical myocardial dysfunction was evaluated.
Incomplete outcome data (attrition bias) ‐ overall survival/overall mortality	Unclear risk	Unclear in how many participants overall survival was evaluated
Incomplete outcome data (attrition bias) ‐ tumour response rate	Low risk	Tumour response evaluated in 100% of all participants in both treatment groups
Incomplete outcome data (attrition bias) ‐ progression‐free survival	Unclear risk	Unclear in how many participants PFS was evaluated
Incomplete outcome data (attrition bias) ‐ toxicities other than cardiac damage with the exception of SMN	Low risk	Toxicities other than cardiac damage evaluated in 100% of all 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 blinding of outcome assessors for some of the outcomes not provided; block randomisation was used). 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 (age and gender comparable, no prior anthracyclines, no prior cardiac dysfunction, stage of disease and prior cardiac irradiation unclear) Difference in length of follow‐up between treatment groups: unclear (length of follow‐up nm)