Correspondence

Cardiotoxicity of Trastuzumab in Clinical Practice

N Engl J Med 2007; 357:94-95July 5, 2007

Article

To the Editor:

Trastuzumab-mediated cardiotoxicity was originally described in women with metastatic breast cancer. The incidence rates were 13% when the antibody was administered in combination with paclitaxel and 27% when it was administered with an anthracycline.1 Cardiotoxicity rates of 1.7 to 4.1% have been reported in several subsequent trials of adjuvant trastuzumab.2-4 However, the incidence of cardiotoxicity among a population of women treated outside of a clinical trial is not known.

In 2005, all women in British Columbia, Canada, with human epidermal growth factor receptor type 2 (HER2)–positive early-stage breast cancer were offered adjuvant trastuzumab either sequentially after their primary chemotherapy or concurrently with four cycles of paclitaxel every 3 weeks given after four cycles of doxorubicin and cyclophosphamide every 3 weeks.5 A total 52-week course of trastuzumab therapy was planned for both the sequential and concurrent strategies (at a dose of 8 mg per kilogram of body weight in cycle 1 and 6 mg per kilogram every 3 weeks thereafter).

The left ventricular ejection fraction (LVEF) was evaluated before trastuzumab administration and every 12 weeks thereafter for the duration of therapy. Trastuzumab was discontinued in women with symptoms and suspected or confirmed cardiac dysfunction. Decisions regarding the continuation of trastuzumab therapy in asymptomatic women were made according to standardized guidelines adopted from the North American adjuvant trastuzumab studies (The National Surgical Adjuvant Breast and Bowel Project B-31 trial [ClinicalTrials.gov number, NCT00004067] and the North Central Cancer Treatment Group Intergroup N9831 trial [ClinicalTrials.gov number, NCT00005970]).3 These guidelines incorporate absolute LVEF declines and the relationship of the LVEF to the institution-specific lower limit of the normal range. When treatment was reinitiated, trastuzumab was administered at a dose of 6 mg per kilogram.

Between July and December 2005, adjuvant trastuzumab therapy was initiated in 155 women. The mean LVEF before trastuzumab treatment was 60.8% in the 102 women who received sequential treatment and 62.3% in the 53 women who received concurrent treatment. Overall, there was no significant difference in the mean LVEF 3, 6, or 9 months after the initiation of trastuzumab treatment in either cohort. However, in the sequential-treatment cohort, 22 women (21.6%) had a cardiac event requiring temporary or permanent discontinuation of trastuzumab: 18 women had an asymptomatic decline in the LVEF, and in 4, suspected or confirmed congestive heart failure developed. Of the 18 women with an asymptomatic decline in the LVEF, 14 received continued treatment with trastuzumab, but in 4 women, trastuzumab was not reinitiated because of a persistently low LVEF. Although 12 of the 14 women who continued to receive trastuzumab successfully completed the planned course of treatment, 2 women had further decreases in the LVEF necessitating permanent discontinuation of the drug. In the concurrent-treatment cohort, one woman had an asymptomatic LVEF decline but was successfully treated again, and symptomatic congestive heart failure developed in one woman.

We cannot account for the high cardiotoxicity rate in our sequential-treatment group as compared with the rate in the pivotal trial of sequential trastuzumab treatment (the Herceptin Adjuvant Trial [ClinicalTrials.gov number, NCT00045032]).2,4 However, most cardiac events in this series were transient, asymptomatic declines in LVEF. Thus, the optimal cardiac monitoring strategy when adjuvant trastuzumab is administered outside of a clinical trial remains uncertain.

Heather L. McArthur, M.D.
Memorial Sloan-Kettering Cancer Center, New York, NY 10003
mcarthuh@mskcc.org

Stephen Chia, M.D.
British Columbia Cancer Agency, Vancouver, BC V5Z 4E6, Canada

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Citing Articles (12)

Citing Articles

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   Xianglin L. Du, Rui Xia, Keith Burau, Chih-Chin Liu. (2011) Cardiac risk associated with the receipt of anthracycline and trastuzumab in a large nationwide cohort of older women with breast cancer, 1998–2005. Medical Oncology 28:S1, 80-90
   CrossRef

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   Luigi Tarantini, Giovanni Cioffi, Stefania Gori, Fausto Tuccia, Lidia Boccardi, Daniella Bovelli, Chiara Lestuzzi, Nicola Maurea, Stefano Oliva, Giulia Russo, Pompilio Faggiano. (2011) Trastuzumab Adjuvant Chemotherapy and Cardiotoxicity in Real-World Women With Breast Cancer. Journal of Cardiac Failure
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   Milayna Subar, WenLong Lin, William Chen, Donald G. Pittman. (2011) Lack of Uniformity in Cardiac Assessment during Trastuzumab Therapy. The Breast Journal 17:4, 383-390
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   Pierantonio Menna, Odalys Gonzalez Paz, Massimo Chello, Elvio Covino, Emanuela Salvatorelli, Giorgio Minotti. (2011) Anthracycline cardiotoxicity. Expert Opinion on Drug Safety1-16
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   Valentina Rossi, Stefania Redana, Andrea Milani, Elena Geuna, Giorgio Valabrega, Massimo Aglietta, Filippo Montemurro. (2011) Trastuzumab in the adjuvant setting: a practical review. Therapy 8:2, 161-177
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   Edith Pituskin, Mark Haykowsky, John R Mackey, Richard B Thompson, Justin Ezekowitz, Sheri Koshman, Gavin Oudit, Kelvin Chow, Joseph J Pagano, Ian Paterson. (2011) Rationale and design of the Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research Trial (MANTICORE 101 - Breast): a randomized, placebo-controlled trial to determine if conventional heart failure pharmacotherapy can prevent trastuzumab-mediated left ventricular remodeling among patients with HER2+ early breast cancer using cardiac MRI. BMC Cancer 11:1, 318
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   Pierantonio Menna, Emanuela Salvatorelli, Carlo Salsano, Luca Gianni, Giorgio Minotti. 2010. Cardiovascular Toxicity of Antitumor Drugs: Translating Molecular Mechanisms into Clinical Facts. , 223-256.
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    (2008) Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiology and Drug Safety 17:1, i-xii
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