Table 2 - uploaded by Stefan Gluck
Content may be subject to copyright.
Summary of Adjuvant Trastuzumab Chemotherapy Trials
Source publication
Anthracyclines are integral components of most adjuvant chemotherapy regimens for surgically removed early breast cancer and are central to the accepted treatment standards. Recently the standard anthracycline regimen of doxorubicin plus cyclophosphamide was found to be inferior in preventing recurrence of breast cancer when compared to cyclophosph...
Context in source publication
Context 1
... the past decade, 5 phase III randomized clinical trials with over 13,000 participants have evaluated the use of trastuzumab in addition to chemotherapy for early- stage breast cancer (Table 2); interim results of these trials have been reported. All the trastuzumab adjuvant trials enrolled patients with HER2-positive (immunohisto- chemistry 3+/fluorescence in situ hybridization [FISH] amplified or chromogenic in situ hybridization amplified) invasive breast cancer resected by lumpectomy or mastec- tomy. ...
Similar publications
Despite advances in surgery, radiotherapy, and chemotherapy, glioblastoma (GBM) remains a malignancy with poor prognosis. The molecular profile of GBM is diverse across patients, and individual responses to therapy are highly variable. Yet, patients diagnosed with GBM are treated with a rather uniform paradigm. Exploiting these molecular difference...
Purpose
We have demonstrated that patients with HER2-amplified tumors derive more benefit from higher doses of doxorubicin-containing chemotherapy (cyclophosphamide, doxorubicin, and fluorouracil [CAF]). Because topoisomerase IIα (Topo-IIα) is a target for doxorubicin and is coamplified in 20% to 50% of HER2-amplified tumors, we postulated that Top...
Opinion statement:
Anthracycline-based regimens have been an important treatment component for patients with breast cancer. As demonstrated in the last Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis, anthracycline-based regimens decrease breast cancer mortality by 20-30%. Anthracycline toxicities include the rare-but pot...
Topoisomerase IIα has been a representative anti-cancer target for decades thanks to its functional necessity in highly proliferative cancer cells. As type of topoisomerase IIα targeting drugs, topoisomerase II poisons are frequently in clinical usage. However, topoisomerase II poisons result in crucial consequences resulted from mechanistically in...
Prediction of response to anthracycline-based therapy for breast cancer is challenging. We aimed to assess the value of HER2 and TOP2A as predictive markers of response to anthracycline-based adjuvant therapy in patients with early breast cancer.
We did a meta-analysis of individual patient data from five randomised adjuvant trials that compared an...
Citations
... Este ensaio comprovou que um regime quimioterapêutico com trastuzumab e sem antraciclinas, no tratamento do cancro da mama, tem uma eficácia antineoplásica equivalente e com menor incidência de eventos cardiotóxicos, quando comparado com regimes terapêuticos adjuvantes com trastuzumab e antraciclinas 67 . Embora outros ensaios confirmem a eficácia desta estratégia terapêutica 68 , atualmente, ainda existem opiniões controversas sobre o papel das antraciclinas no tratamento combinado antineoplásico 69 . Conjugados trastuzumab-toxinas. ...
Cardiotoxicity is one of the most significant adverse effects of cancer treatment, and is responsible for considerable morbidity and mortality. Among the effects of chemotherapeutic agents on the cardiovascular system, the most frequent and serious is heart failure with ventricular systolic dysfunction. Other toxic effects include hypertension, thromboembolic disease, pericardial disease, arrhythmias and myocardial ischemia. For several decades, cancer therapy-induced cardiomyopathy was almost exclusively associated with the use of cumulative doses of anthracyclines, which cause permanent damage at the cellular level. However, new therapeutic agents, such as the monoclonal antibody trastuzumab, induce transient reversible myocyte dysfunction which is unrelated to the dose used. Early identification of potential cardiovascular injury, accurate diagnosis of cardiotoxic events and implementation of appropriate monitoring plans are essential in patients with cancer. Close cooperation between cardiologists and oncologists is thus crucial, in order to balance the risks and benefits of cardiotoxic anticancer therapy. In this article we review the various responses to cardiotoxic cancer treatments and their relationship with the main antineoplastic drugs used in clinical practice. In addition, we discuss the main guidelines on detection and monitoring of cardiotoxicity in patients with cancer.
... 67 Although other trials have confirmed the efficacy of this approach, 68 there are conflicting opinions regarding the role of anthracyclines in combined cancer treatments. 69 Trastuzumab-toxin conjugates. Monoclonal antibodies that are tumor-specific but insufficiently cytotoxic in themselves can be chemically bound to cytotoxic agents to direct them to specific antigens on target tumors, which confers more control over apoptosis in tumor cells and greater selectivity in their action. ...
Cardiotoxicity is one of the most significant adverse effects of cancer treatment, and is responsible for considerable morbidity and mortality. Among the effects of chemotherapeutic agents on the cardiovascular system, the most frequent and serious is heart failure with ventricular systolic dysfunction. Other toxic effects include hypertension, thromboembolic disease, pericardial disease, arrhythmias and myocardial ischemia. For several decades, cancer therapy-induced cardiomyopathy was almost exclusively associated with the use of cumulative doses of anthracyclines, which cause permanent damage at the cellular level. However, new therapeutic agents, such as the monoclonal antibody trastuzumab, induce transient reversible myocyte dysfunction which is unrelated to the dose used. Early identification of potential cardiovascular injury, accurate diagnosis of cardiotoxic events and implementation of appropriate monitoring plans are essential in patients with cancer. Close cooperation between cardiologists and oncologists is thus crucial, in order to balance the risks and benefits of cardiotoxic anticancer therapy. In this article we review the various responses to cardiotoxic cancer treatments and their relationship with the main antineoplastic drugs used in clinical practice. In addition, we discuss the main guidelines on detection and monitoring of cardiotoxicity in patients with cancer.
... In addition, updated results from the US Oncology 9735 (USO-9735) study questioned the place in therapy of anthracyclines in early breast cancer (Jones et al., 2009b). At present, there are conflicting opinions on the role of anthracyclines in the adjuvant setting (Castrellon & Gluck, 2008;Gianni & Valagussa, 2009). The optimization of anthracycline-taxane schedules has been proposed as a way forward . ...
Drug-induced cardiotoxicity is emerging as an important issue among cancer survivors. For several decades, this topic was almost exclusively associated with anthracyclines, for which cumulative dose-related cardiac damage was the limiting step in their use. Although a number of efforts have been directed towards prediction of risk, so far no consensus exists on the strategies to prevent and monitor chemotherapy-related cardiotoxicity. Recently, a new dimension of the problem has emerged when drugs targeting the activity of certain tyrosine kinases or tumor receptors were recognized to carry an unwanted effect on the cardiovascular system. Moreover, the higher than expected incidence of cardiac dysfunction occurring in patients treated with a combination of old and new chemotherapeutics (e.g. anthracyclines and trastuzumab) prompted clinicians and researchers to find an effective approach to the problem. From the pharmacological standpoint, putative molecular mechanisms involved in chemotherapy-induced cardiotoxicity will be reviewed. From the clinical standpoint, current strategies to reduce cardiotoxicity will be critically addressed. In this perspective, the precise identification of the antitarget (i.e. the unwanted target causing heart damage) and the development of guidelines to monitor patients undergoing treatment with cardiotoxic agents appear to constitute the basis for the management of drug-induced cardiotoxicity.
With the introduction of anthracycline-based regimens, 5-year survival rates have significantly improved in patients with early-stage breast cancer. With the addition of trastuzumab, a monoclonal antibody targeting the human epidermal growth factor receptor-2 (HER2), improvements in overall survival have been observed among patients with advanced HER2-positive disease. Subsequently, lapatinib, an orally bioavailable small molecule dual HER2- and EGFR/HER1-specific tyrosine kinase inhibitor, received Food and Drug Administration (FDA) approval in combination with capecitabine for patients with advanced HER2+ breast cancer. Then, pertuzumab in 2012 and ado-trastuzumab emtansine in 2013 were approved in the US and elsewhere based on evidence showing an improvement in survival outcomes in patients with mostly trastuzumab naïve or trastuzumab-exposed metastatic disease. The FDA also approved 1 year of extended adjuvant neratinib after chemotherapy and a year of trastuzumab for HER2-positive breast cancer on the basis of the ExteNET trial. The clinical benefit demonstrated by those drugs in advanced disease has triggered several adjuvant and neoadjuvant trials testing them in combination with chemotherapy, but also without conventional chemotherapy, using single or dual HER2-targeting drugs. In this article, we review the current data on the therapeutic management of HER2-positive early-stage breast cancer in the adjuvant and neoadjuvant setting. We also review the data the efficacy and safety of anthracycline-based and nonanthracycline-based adjuvant chemotherapy regimens combined with trastuzumab, and optimum chemotherapy regimens in small HER2-positive tumors.
The longer mean survival of oncological patients has led to an increased incidence of chemotherapy-induced cardiomyopathy. Anthracyclines and trastuzumab are the two most commonly implicated agents. Anthracyclines cause irreversible type I cardiomyopathy, where as, trastuzumab causes a potentially reversible type II cardiomyopathy. The most important risk factors are the total cumulative dose and pre-existing cardiovascular disease. MUGA scan and transthoracic echocardiogram are the most commonly used modalities to evaluate left ventricular function. Routine screening must be performed in all patients receiving cardiotoxic drugs. Early detection and treatment is critical for improved long-term cardiovascular prognosis. Patients with cardiomyopathy should be treated with standard heart failure therapy and treatment should be initiated as early as possible. Cardiac resynchronization therapy and heart transplant are viable options for patients with advanced heart failure. There is a great need for more research in this field with goals to develop drugs and protocols with lower cardiotoxicity, which still maintain antitumor efficacy; to develop biomarkers and imaging techniques for early detection of cardiac dysfunction; and to develop better management strategies of patients with cardiomyopathy. Creation of dedicated cardiac-oncology centers is essential for an improved future in this field.
