Is it safe to give anthracyclines concurrently with trastuzumab in neo-adjuvant or metastatic settings for HER2-positive breast cancer? A meta-analysis of randomized controlled trials
Abstract:Concurrent use of anthracyclines and trastuzumab used to be avoided in the treatment of HER2-positive breast cancer due to the high risk of cardiac toxicity. However, several newly published studies challenged this view and demonstrated that concomitant use of the two agents significantly improved the clinical outcome without causing additional cardiac toxicity. This meta-analysis summarized available data to investigate the safety and efficacy of concurrent use of anthracyclines and trastuzumab. Eligible stud… Show more
“…In addition, 2 patients received adjuvant treatment with a slightly different dosing schedule, and 4 patients were treated with the anti-HER2/neu antibody trastuzumab. Cardiac toxicity could be more serious when HER2/neu-targeting agents are combined with anthracyclines [28][29][30]. Our findings, however, are in line with a novel study showing that a combination of docetaxel with trastuzumab has no additional effect on the QT interval [31].…”
Background: Chemotherapy with anthracyclines is associated with life-threatening electrocardiographic alterations including corrected QT (QTc) interval prolongation. Patients and Methods: In this study we assessed the effect of epirubicin, cyclophosphamide, and docetaxel (EC-Doc) on the QTc interval in 10 patients with early breast cancer. Cardiac toxicity was assessed with symptoms, transthoracic echocardiography, electrocardiography (ECG), and serum cardiac markers at baseline and after 4 cycles of EC and 4 cycles of docetaxel. To evaluate the influence of interobserver variation, the QTc interval was analyzed by a cardiologist, a gynecologist, and with automated ECG interpretation software. Results: There was a significant QTc prolongation after EC treatment independent of the investigator. In addition, a significant increase in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels was noted after EC treatment. QTc prolongation and NT-proBNP levels normalized after docetaxel treatment. Other biochemical markers were within normal ranges. No clinically relevant effect on left ventricular ejection fraction was observed. Conclusion: This prospective study demonstrated that EC treatment increases the QTc interval and NT-proBNP levels in women with early breast cancer. This effect was reversible and independent of docetaxel administration. Moreover, the treating physician can safely perform QTc interval evaluation as part of clinical routine independent of his/her specialty. Due to the small number of patients, further conclusions are limited at this point.
“…In addition, 2 patients received adjuvant treatment with a slightly different dosing schedule, and 4 patients were treated with the anti-HER2/neu antibody trastuzumab. Cardiac toxicity could be more serious when HER2/neu-targeting agents are combined with anthracyclines [28][29][30]. Our findings, however, are in line with a novel study showing that a combination of docetaxel with trastuzumab has no additional effect on the QT interval [31].…”
Background: Chemotherapy with anthracyclines is associated with life-threatening electrocardiographic alterations including corrected QT (QTc) interval prolongation. Patients and Methods: In this study we assessed the effect of epirubicin, cyclophosphamide, and docetaxel (EC-Doc) on the QTc interval in 10 patients with early breast cancer. Cardiac toxicity was assessed with symptoms, transthoracic echocardiography, electrocardiography (ECG), and serum cardiac markers at baseline and after 4 cycles of EC and 4 cycles of docetaxel. To evaluate the influence of interobserver variation, the QTc interval was analyzed by a cardiologist, a gynecologist, and with automated ECG interpretation software. Results: There was a significant QTc prolongation after EC treatment independent of the investigator. In addition, a significant increase in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels was noted after EC treatment. QTc prolongation and NT-proBNP levels normalized after docetaxel treatment. Other biochemical markers were within normal ranges. No clinically relevant effect on left ventricular ejection fraction was observed. Conclusion: This prospective study demonstrated that EC treatment increases the QTc interval and NT-proBNP levels in women with early breast cancer. This effect was reversible and independent of docetaxel administration. Moreover, the treating physician can safely perform QTc interval evaluation as part of clinical routine independent of his/her specialty. Due to the small number of patients, further conclusions are limited at this point.
“…However, when addressing toxicity, the authors observed that concurrent administration was indeed associated with significantly increased risk of cardiac-related adverse events. Subgroup analysis confirmed this finding both in the neoadjuvant and metastatic setting (Du et al, 2014). Currently, the use of trastuzumab concomitantly with an anthracyclinecontaining regimen is not recommended because of the potential for increased cardiotoxicity (Denduluri et al, 2016).…”
To report the results of the DECT trial, a phase II study of locally advanced or operable HER2-positive breast cancer (BC) treated with taxanes and concurrent anthracyclines and trastuzumab. Eligible patients (stage IIA-IIIB HER2-positive BC, 18-75 years, normal organ functions, ECOG 1, and left ventricular ejection fraction (LVEF) !55%) received four cycles of neoadjuvant docetaxel, 100 mg/m 2 intravenously, plus trastuzumab 6 mg/kg (loading dose 8 mg/kg) every 3 weeks, followed by four 3-weekly cycles of epirubicin 120 mg/m 2 and cyclophosphamide, 600 mg/m 2 , plus trastuzumab. Primary objective was pathologic complete response (pCR) rate, defined as ypT0/is ypN0 at definitive surgery. We enrolled 45 consecutive patients. All but six patients (13.3%) completed chemotherapy and all underwent surgery. pCR was observed in 28 patients (62.2%) overall and in 6 (66.7%) from the inflammatory subgroup. The classification and regression tree analysis showed a 100% pCR rate in patients with BMI !25 and with hormone negative disease. The median follow up was 46 months (8-78). Four-year recurrencefree survival was 74.7% (95%CI, 58.2-91.2). Seven patients (15.6%) recurred and one died. Treatment was well tolerated, with limiting toxicity being neutropenia. No clinical cardiotoxicity was observed. Six patients (13.4%) showed a transient LVEF decrease (<10%). In one patient weThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.L. Pizzuti and M. Barba contributed equally to this work.
Conflicts of interest:The authors declare that they have no conflict of interest.
“…This same regimen should be considered for elderly patients with a risk of taxane toxicity. Generically, combining anthracyclines with trastuzumab is not recommended, since it increases the risk of cardiotoxicity [52] If the patient relapses within the first 6 months after completing the trastuzumab adjuvant treatment, the first-line treatment with T-DM1 is recommended, since it has shown a median PFS and OS of 15.2–29.8 months, respectively, and appears to be less toxic than lapatinib combined with capecitabine [39, 53] (SEOM level of certainty: moderate; strength of recommendation: B).Fig. 5Proposed treatment for patients with HER2-positive breast cancer
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Metastatic breast cancer is a heterogeneous disease that presents in varying forms, and a growing number of therapeutic options makes it difficult to determine the best choice in each particular situation. When selecting a systemic treatment, it is important to consider the medication administered in the previous stages, such as acquired resistance, type of progression, time to relapse, tumor aggressiveness, age, comorbidities, pre-and post-menopausal status, and patient preferences. Moreover, tumor genomic signatures can identify different subtypes, which can be used to create patient profiles and design specific therapies. However, there is no consensus regarding the best treatment sequence for each subgroup of patients. During the SABCC Congress of 2014, specialized breast cancer oncologists from referral hospitals in Europe met to define patient profiles and to determine specific treatment sequences for each one. Conclusions were then debated in a final meeting in which a relative degree of consensus for each treatment sequence was established. Four patient profiles were defined according to established breast cancer phenotypes: pre-menopausal patients with luminal subtype, post-menopausal patients with luminal subtype, patients with triple-negative subtype, and patients with HER2-positive subtype. A treatment sequence was then defined, consisting of hormonal therapy with tamoxifen, aromatase inhibitors, fulvestrant, and mTOR inhibitors for pre-and post-menopausal patients; a chemotherapy sequence for the first, second, and further lines for luminal and triple-negative patients; and an optimal sequence for treatment with new antiHER2 therapies. Finally, a document detailing all treatment sequences, that had the agreement of all the oncologists, was drawn up as a guideline and advocacy tool for professionals treating patients with this disease.
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