Cardiac Toxicity From Systemic Cancer Therapy: A Comprehensive Review
Section snippets
Left ventricular dysfunction
Left ventricular dysfunction (LVD) is associated with exposure to several anticancer therapies. An early definition of the effect of cancer therapy on LV function has been promulgated by the Cardiac Review and Evaluation Committee supervising trastuzumab (Herceptin) clinical trials.1 According to this definition, cardiomyopathy is characterized by a “decrease in cardiac left ventricular ejection fraction (LVEF) that was either global or more severe in the septum; (2) symptoms of congestive
Cardiac ischemia
Although cardiac ischemia related to chemotherapy administration is an unusual occurrence, an increased risk of acute coronary syndrome has been associated with administration of cytotoxic and targeted agents for cancer treatment.
Hypertension
Multiple investigative and clinical observations have demonstrated hypertension to be a common class effect resulting from treatment with VEGF inhibitors.75 Rates of significant hypertension appear to depend on the antiangiogenic agent used, the tumor type, and patient-related factors including age and comorbidity (Table 3). In the major trials using bevacizumab, rates of significant toxicity ranged from 7% to 36%.42, 45, 46, 47 The degree of hypertension associated with the VEGFR tyrosine
QT prolongation
Prolongation of the QT interval can lead to life-threatening cardiac arrhythmias, including “torsades de pointes” (TdP). Although prolongation of the QT interval is not the best predictor of proarrhythmic risk, it represents the principal clinical surrogate marker by which to evaluate the arrhythmic risk of a drug; and it has led to withdrawal of several anticancer drugs from the market. Although drugs leading to prolonged QT may possess significant risks of serious adverse events, the clinical
Conclusions
Within the oncologic toolbox are both traditional and novel anticancer agents with the potential to induce cardiac toxicity. Oncologists thus have had to develop the ability to identify and manage complicated cardiac risks in clinical investigations and in general practice. Many highly effective agents in contemporary oncology, including anthracyclines and trastuzumab, are associated with well-described risks of short- and long-term cardiac events. As these agents are often used with curative
Statement of Conflict of Interest
All authors declare that there are no conflicts of interest.
References (108)
- et al.
Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer
Ann Oncol
(2004) - et al.
Cyclophosphamide cardiotoxicity: an analysis of dosing as a risk factor
Blood
(1986) - et al.
Weekly paclitaxel as first-line chemotherapy in elderly advanced breast cancer patients: a phase II study of the Gruppo Italiano di Oncologia Geriatrica (GIOGer)
Ann Oncol
(2005) - et al.
Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort
Lancet
(2010) Vascular endothelial growth factor in breast cancer: biologic and therapeutic aspects
Semin Oncol
(2002)- et al.
Cardiac safety of lapatinib: pooled analysis of 3689 patients enrolled in clinical trials
Mayo Clin Proc
(2008) - et al.
Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial
Lancet
(2006) - et al.
Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate
Ann Oncol
(2008) - et al.
Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib
Lancet
(2007) - et al.
Incidence of cardiotoxicity with the oral fluoropyrimidine capecitabine is typical of that reported with 5-fluorouracil
Ann Oncol
(2002)
Acute coronary syndrome induced by oral capecitabine
Can J Cardiol
Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis
Lancet Oncol
Management of hypertension in angiogenesis inhibitor-treated patients
Ann Oncol
Hypertension as a predictive factor of sunitinib activity
Ann Oncol
Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation
Ann Oncol
Cardiac dysfunction in the trastuzumab clinical trials experience
J Clin Oncol
Cardiac toxicity in breast cancer survivors: review of potential cardiac problems
Clin Cancer Res
Risk factors for doxorubicin-induced congestive heart failure
Ann Intern Med
Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer
J Clin Oncol
Epidemiology of anthracycline cardiotoxicity in children and adults
Semin Oncol
Iron signaling and oxidant damage
Cardiovasc Toxicol
Adriamycin-induced interference with cardiac mitochondrial calcium homeostasis
Cardiovasc Toxicol
Role of mtDNA lesions in anthracycline cardiotoxicity
Cardiovasc Toxicol
Anthracycline induced phospholipase A2 inhibition
Cardiovascular Toxicology
Antioxidant defense against anthracycline cardiotoxicity by metallothionein
Cardiovasc Toxicol
Cyclophosphamide cardiotoxicity in bone marrow transplantation: a prospective evaluation of new dosing regimens
J Clin Oncol
Cardiotoxicity associated with high-dose cyclophosphamide therapy
Arch Intern Med
High-dose ifosfamide is associated with severe, reversible cardiac dysfunction
Ann Intern Med
Chemotherapy-induced cardiotoxicity: current practice and prospects of prophylaxis
Eur J Heart Fail
Adjuvant docetaxel for node-positive breast cancer
N Engl J Med
Sorafenib in advanced clear-cell renal-cell carcinoma
N Engl J Med
Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC->T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC->TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients: BCIRG 006 Study. San Antonio 2009 Annual Breast Cancer meeting
Cancer Res
Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer
N Engl J Med
Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer
N Engl J Med
Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2
N Engl J Med
Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31
J Clin Oncol
Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer
N Engl J Med
Cardiac toxicity with anti-HER-2 therapies: what have we learned so far?
Target Oncol
Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer
J Clin Oncol
Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial
J Clin Oncol
Cardiotoxicity of trastuzumab in clinical practice
N Engl J Med
Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 Adjuvant Breast Cancer Trial
J Clin Oncol
Modulation of anthracycline-induced myofibrillar disarray in rat ventricular myocytes by neuregulin-1beta and anti-erbB2: potential mechanism for trastuzumab-induced cardiotoxicity
Circulation
Requirement for neuregulin receptor erbB2 in neural and cardiac development
Nature
ErbB2 is essential in the prevention of dilated cardiomyopathy
Nat Med
Herceptin and the heart—a molecular modifier of cardiac failure
N Engl J Med
Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment
J Clin Oncol
Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the MD Anderson Cancer Center experience
J Clin Oncol
Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial
J Clin Oncol
The biology of VEGF and its receptors
Nat Med
Cited by (0)
Statement of Conflict of Interest: see page 101.
- 1
The first 2 authors equally contributed to the manuscript.