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Trastuzumab, paclitaxel linked to low cardiac toxicity rates in early-stage breast cancer
Weekly adjuvant treatment with paclitaxel and trastuzumab lead to low incidence of grade 3 or grade 4 left ventricular systolic dysfunction and asymptomatic left ventricular ejection fraction decline among patients with early-stage human epidermal growth factor receptor 2-positve breast cancer, according to study results.
Because of the relatively rare occurrence of serious adverse events, left ventricular ejection fraction (LVEF) monitoring during trastuzumab (Herceptin, Genentech) therapy likely can be simplified for many patients, according to the researchers.
Despite its life-saving benefit, trastuzumab is associated with symptomatic and asymptomatic LVEF decline, according to study background.
Thus, Chau Dang, MD, chief of the medical oncology service at Memorial Sloan Kettering Cancer Center, and colleagues sought to observe the cardiac adverse events associated with combined paclitaxel and trastuzumab treatment in patients with node-negative, human epidermal growth factor 2 (ERBB2)-positive breast cancer. Further, Dang and colleagues evaluated the utility of LVEF monitoring in this patient population.
The researchers performed a secondary analysis of an uncontrolled, single-arm study of 406 patients (median age, 55 years; range, 24-85) with ERBB2-positive breast cancer. All patients had tumors 3 cm or smaller and a baseline LVEF of at least 50%.
Patients received 80 mg/m2 adjuvant paclitaxel for 12 weeks with trastuzumab, with trastuzumab continuing for 1 year. During the monotherapy phase, patients received trastuzumab weekly (2 mg/kg) every 3 weeks (6 mg/kg).
Cardiac safety — including grade 3 to grade 4 left ventricular systolic dysfunction and significant asymptomatic LVEF decline — served as the primary endpoint. The researchers assessed LVEF at baseline, 12 weeks, 6 months and 1 year.
Median follow-up was 4 years.
Eighty-eight percent of patients (n = 356) completed approximately 1 year of protocol therapy.
Two patients (0.5%; 95% CI, 0.1-1.8) developed grade 3 left ventricular systolic dysfunction, resulting in treatment cessation.
Further, 13 patients (3.2%; 95% CI, 1.9-5.4) had significantly asymptomatic LVEF; however, 11 patients remained on study.
Median LVEF was 65% at baseline, 64% at 12 weeks, 64% at 6 months and 64% at 1 year.
Dang and colleagues acknowledged limitations of their study, including the exclusion of patients at high risk for LVEF from the initial study. Further, they noted that emerging cardiac research has suggested that LVEF may not serve as the best marker of cardiac contractility.
“A prospective trial to include a uniform assessment and management of cardiovascular risk factors, as well as a central review of LVEF data in patients receiving a non–anthracycline regimen, will be needed to help further define which patients may require less intensive LVEF monitoring,” Dang and colleagues wrote.
In an accompanying editorial, Gerard Milano, PhD, Emmanuel Chamorey, PharmD, PhD, and Jean-Marc Ferrero, MD, PhD, all of Centre Antoine-Lacassagne in Nice, France, identified further study limitations.
“Three other important criteria should have been taken into account: BMI, nicotine intoxication and menopausal status,” they wrote. “The [researchers] stress that the management of deterioration in LVEF were left to the physician’s discretion, thus introducing a further variability factor.”
However, Milano, Chamorey and Ferrero noted that further research evaluating the effects of therapy on cardiac function in this population is needed.
“A prospectively, properly designed, confirmatory study focused on the cardiac impact of this treatment remains necessary to obtain more precise information on these adverse effects,” they wrote. – by Cameron Kelsall
Disclosure: Dang reports research funding from Genentech/Roche and GlaxoSmithKline. Please see the full study for a list of all other researchers’ relevant financial disclosures. Milano reports honoraria from GlaxoSmithKline and Roche, as well as a consultant role with Roche. Chamorey and Ferrero report no relevant financial disclosures.
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Dang C, et al. JAMA Oncol. 2015;doi:10.1001/jamaoncol.2015.3709.
Milano G, et al. JAMA Oncol. 2015;doi:10.1001/jamaoncol.2015.3866.