Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility.
OBJECTIVE
To assess the spectrum and reversibility of the cardiotoxicity observed in the adjuvant trastuzumab trials.


METHODS
The design and efficacy of the major adjuvant trastuzumab trials was assessed, including the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31, North Central Cancer Treatment Group N9831, Herceptin Adjuvant, Breast Cancer International Research Group 006, and Finland Herceptin trials. The cardiotoxicity data were evaluated with a focus on the follow-up cardiac evaluations of women who were diagnosed with cardiotoxicity. Proposed mechanisms of trastuzumab-related cardiotoxicity were considered. The natural history of congestive heart failure (CHF) was reviewed with the goal of placing the trastuzumab experience in context.


RESULTS
Up to 4% of patients enrolled onto the adjuvant trastuzumab trials experienced severe CHF during treatment. In these trials, early stopping rules that identified an unacceptable level of cardiotoxicity were never reached. Despite this, a large number of patients on these trials experienced some form of cardiotoxicity that ultimately required discontinuation of trastuzumab. Approximately 14% of patients in the NSABP B-31 trial discontinued trastuzumab because of asymptomatic decreases in left ventricular ejection fraction (LVEF). Results of follow-up cardiac evaluations of patients diagnosed with any degree of cardiotoxicity in the NSABP B-31 trial document that a clinically significant proportion of patients have sustained decrements in their LVEF to less than 50%.


CONCLUSIONS
Adjuvant trastuzumab provides substantial benefits to patients with human epidermal growth factor receptor 2-positive breast cancer, however, competing immediate and long-term cardiovascular risks are a great concern. Continued cardiac follow-up of these women is of critical importance.
Department of Medicine, Division of Medical Oncology, Stanford University, Stanford, CA, USA. guardino@stanford.edu.
Melinda L
ML
Telli
Sharon A
SA
Hunt
Robert W
RW
Carlson
Alice E
AE
Guardino
D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000150:complications / Q000188:drug therapy*; D002986:Clinical Trials as Topic; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005500:Follow-Up Studies; D006321:Heart / Q000187:drug effects*; D006331:Heart Diseases / Q000139:chemically induced*; D006333:Heart Failure / Q000139:chemically induced* / Q000188:drug therapy; D006801:Humans; D008875:Middle Aged; D000068878:Trastuzumab; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced* / Q000188:drug therapy
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068878:Trastuzumab