New insight into epirubicin cardiac toxicity: competing risks analysis of 1097 breast cancer patients.
BACKGROUND
Current recommendations that cancer patients receive a maximum cumulative dose of 900 mg/m(2) epirubicin are based on the risk of epirubicin-mediated cardiotoxicity and do not take into account the competing risk of death from cancer. Here, we identify risk factors for cardiotoxicity and overall mortality and determine the cumulative dose of epirubicin that yields a 5% risk for cardiotoxicity for cancer patients from different risk backgrounds.


METHODS
Data were collected from 1097 consecutive anthracycline-naive patients treated for metastatic breast cancer with epirubicin. Patients who developed congestive heart failure classified as New York Heart Association class 2 or higher were recorded as having cardiotoxicity. Independent Cox multiple regression analyses for cardiotoxicity and for overall mortality were followed by competing risks analysis, with cardiotoxicity as the primary event and death from all other causes as the competing event. All statistical tests were two-sided.


RESULTS
A total of 11.4% of patients developed cardiotoxicity. Risk factors for cardiotoxicity included increased cumulative dose of epirubicin (hazard ratio per every 100 mg/m(2) administered = 1.40, 95% confidence interval = 1.21 to 1.61), patient age, predisposition to cardiac disease, history of mediastinal irradiation, or antihormonal treatment for metastatic disease. Risk factors for death from all other causes (including breast cancer) included lesser dosages of epirubicin, increased tumor burden, prior use of adjuvant chemotherapy, and patient age. The cumulative dosage of epirubicin that carries a 5% risk of cardiotoxicity was lower than previously assumed and was dependent on risks of both cardiotoxicity and overall mortality.


CONCLUSIONS
Maximum cumulative dosages of epirubicin are presented that confer a 5% risk of cardiotoxicity for patients with different sets of risk factors.
Ryberg
Marianne
M
Department of Oncology, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2730 Herlev, Denmark. mary@heh.regionh.dk
Nielsen
Dorte
D
Cortese
Giuliana
G
Nielsen
Gitte
G
Skovsgaard
Torben
T
Andersen
Per Kragh
PK
D000328:Adult; D000367:Age Factors; D000368:Aged; D018943:Anthracyclines / Q000009:adverse effects; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D003718:Denmark / Q000453:epidemiology; D004198:Disease Susceptibility; D004334:Drug Administration Schedule; D015251:Epirubicin / Q000008:administration & dosage* / Q000009:adverse effects*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006333:Heart Failure / Q000139:chemically induced* / Q000503:physiopathology; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis; D016016:Proportional Hazards Models; D018714:Radiotherapy, Adjuvant; D012189:Retrospective Studies; D012307:Risk Factors; D012720:Severity of Illness Index; D013629:Tamoxifen / Q000008:administration & dosage; D014751:Vindesine / Q000008:administration & dosage
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D013629:Tamoxifen; D015251:Epirubicin; D003520:Cyclophosphamide; D002945:Cisplatin; D014751:Vindesine; D005472:Fluorouracil; D008727:Methotrexate