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Herceptin Heart Risks Clarified for Older Patients

http://www.medpagetoday.com/HematologyOncology/BreastCancer/27975

By Charles Bankhead, Staff Writer, MedPage Today
Published: August 10, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Older breast cancer patients with heart disease or diabetes have a significantly increased risk of cardiotoxicity when treated with trastuzumab (Herceptin), according to data from a single-center chart review.
More than a fourth of patients had clinically significant declines in left ventricular ejection fraction (LVEF) during treatment with the anti-HER2 antibody. Two-thirds of the episodes (8 of 12) were asymptomatic.
Of the four patients who developed symptomatic congestive heart failure (CHF), three recovered heart function over several weeks, but one patient did not regain cardiac function despite stopping trastuzumab and receiving standard CHF therapy, as reported online in Annals of Oncology. Action Points Explain that older breast cancer patients with heart disease or diabetes have a significantly increased risk of cardiotoxicity when treated with trastuzumab (Herceptin).

Point out that around one-quarter of the patients had a cardiac event that had a time to onset ranging from three to 132 weeks after the start of trastuzumab-based therapy, and was not always reversible.

Even though most declines in heart function were asymptomatic and all but one patient regained function, the findings point to a need for caution, the authors noted.

"The fact that the mortality rate at five years after diagnosis of CHF is approximately 50% in patients older than 65 years warrants close surveillance of early symptoms and cardiac function in the elderly breast cancer population to be treated with trastuzumab," Cesar Serrano, MD, of Vall d'Hebron University Hospital in Barcelona, and coauthors wrote in conclusion.
Cardiotoxicity was an unanticipated adverse effect of trastuzumab. As as result, initial clinical trials of the agent did not mandate monitoring of cardiac function, according to the article's background. Moreover, studies that did require monitoring employed different types and intervals of monitoring, complicating efforts to compare or combine results.
In contrast to anthracycline-related cardiotoxicity, the adverse effects of trastuzumab are neither dose related nor cumulative. The severity of trastuzumab-related cardiotoxicity varies widely but usually is reversible with discontinuation of the drug, the authors continued.

A limitation of many clinical trials in oncology is the inclusion of few older patients. With respect to trastuzumab, clinical trials in breast cancer generally limited participation to women 65 or younger and with good performance status. Therefore, extrapolation of results to older or sicker patients requires caution, the authors wrote.

Given the benefits of trastuzumab and the lack information about cardiotoxicity in older patients, Serrano and coauthors reviewed their own clinical experience with the agent.

Examination of medical records revealed 45 breast cancer patients age 70 or older treated with trastuzumab. The patients' median age at the start of trastuzumab was 75.9, and 11 patients were older than 80. About 90% of the patients had performance status 0-1, 56% received neoadjuvant or adjuvant trastuzumab, and the remaining 44% received the drug for metastatic disease.

Assessment of LVEF was performed at baseline and after a median interval of 4.5 months. The baseline LVEF averaged 64%. Median duration of trastuzumab treatment was 49 weeks.

The authors found that 12 (26.7%) patients had a cardiac event that had a time to onset ranging from three to 132 weeks after the start of trastuzumab-based therapy. Every patient had at least one risk factor for cardiac disease and eight had two or more risk factors.

The four patients who developed symptomatic CHF had stage IV breast cancer. Their baseline LVEF values ranged from 50.8% to 70%, and the time to onset of CHF was three, five, nine, and 72 weeks. Trastuzumab was discontinued in all cases, and the time to recovery in three patients was three, five, and 21 weeks.

The one patient who did not recover heart function had the latest onset of symptomatic heart failure, one risk factor for heart disease, and a baseline LVEF of 63.8%.

The eight patients with asymptomatic declines in LVEF included five patients with stage IV cancer. The number of cardiac risk factors ranged from one to six, with baseline LVEF ranging from 57% to 71.8%. The time to recovery of heart function was nine weeks or less in six of the eight patients.

Comparison of patients with and without cardiotoxicity showed no differences in treatment duration, baseline LVEF, history of anthracycline therapy, or left-sided radiation therapy.

In general, patients who developed cardiotoxicity during trastuzumab therapy had more cardiac risk factors. However, only two factors remained statistically significant in a multivariate analysis: pre-existing cardiac disease or disorders (P=0.017) and diabetes (P=0.010).

Obesity was a significant factor in univariate analysis but dropped out in the multivariate analysis, and other conventional risk factors such as dyslipidemia and hypertension failed to make the cut in either analysis.

"The incidence of cancer increases greatly with age and about 70% of all newly diagnosed cancers are in patients older than 65 years," the authors noted in their discussion.

"Given the expected increase in the absolute number of elderly cancer patients over the coming decades, information about efficacy and safety of anticancer treatments is needed in this population, as to date, they have been frequently excluded from pivotal studies."

The authors advised caution when interpreting the data. They noted the small sample size and the "very limited power to detect small differences in multivariate analysis."

The authors had no relevant disclosures.

Primary source: Annals of Oncology
Source reference:
Serrano C et al. "Trastuzumab-related cardiotoxicity in the elderly: A role for cardiovascular risk factors" Ann Oncol 2011; DOI: 10.1093/annonc/mdr348