Anticancer drugs and cardiotoxicity: Insights and perspectives in the era of targeted therapy

Pharmacology & Therapeutics 125 (2010) 196–218

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Pharmacology & Therapeutics j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p h a r m t h e r a

Associate editor: P. Holzer

Anticancer drugs and cardiotoxicity: Insights and perspectives in the era of targeted therapy Emanuel Raschi a, Valentina Vasina a, Maria Grazia Ursino a, Giuseppe Boriani b, Andrea Martoni c, Fabrizio De Ponti a,⁎ a b c

Department of Pharmacology, University of Bologna, Bologna, Italy Institute of Cardiology, University of Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy Medical Oncology Unit, Azienda Ospedaliero-Universitaria di Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy

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a b s t r a c t 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. © 2009 Elsevier Inc. All rights reserved.

Keywords: Cardiac toxicity Monitoring Chemotherapy Target Antitarget

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anthracycline-induced cardiotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cardiotoxicity of targeted drugs: the heart as an antitarget . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: ABL, Abelson tyrosine kinase; ADCC, antibody-dependent cell-mediated cytotoxicity; ALTTO, Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial; AMPK, AMP-activated protein kinase; ASCO, American Society of Clinical Oncology; ASK1, apoptosis signal-regulating kinase; AUC, area under curve; BAX, Bcl 2 associated X protein; BCIRG 006, Breast Cancer International Research Group; BCR, breakpoint cluster region; BETH, Bevacizumab and Trastuzumab Adjuvant Therapy in HER-2-Positive Breast Cancer study; BNP, brain natriuretic peptide; CCSS, Childhood Cancer Survivor Study; CHERLOB, Preoperative Chemotherapy plus Lapatinib or Trastuzumab or Both in HER2-positive Operable Breast Cancer trial; CHF, chronic heart failure; CREC, Cardiac Review and Evaluation Committee; CSF1R, colony-stimulating factor 1 receptor; cTnT, cardiac troponin; DNR, daunorubicin; DOX, doxorubicin; DOXOL, doxorubicinol; DTX, docetaxel; E/A, mitral inflow pattern early/atrial ratio; ECHO, echocardiography; ECOG E2198, Eastern Cooperative Oncology Group trial; EGFR, epidermal growth factor receptor; EIF2α, eukaryotic translation initiation factor 2α; EPI, epirubicin; EPIOL, epirubicinol; ER, endoplasmic reticulum; ERBB2, see HER2; ERBB4, see HER4; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; FDA, Food and Drug Administration; FEC, cyclophosphamide; FinHer, Finland Herceptin trial; FLT, FMS-related tyrosine kinase 3; GH, growth hormone; GIST, gastrointestinal stromal tumor; HCC, hepatocellular carcinoma; HER2, human epidermal growth factor receptor 2; HER4, human epidermal growth factor receptor 4; HERA, Herceptin Adjuvant trial; IRE 1, inositol-requiring enzyme 1; IRP, iron regulatory protein; JAK, janus kinase; JNK, jun N-terminal kinase; LDOXO, liposomal doxorubicin; LVEF, left ventricular ejection fraction; MAPK, mitogen-activated protein kinase; MRCC, metastatic renal cell carcinoma; MST2, mammalian sterile 20 kinase 2; MUGA, radionuclide ventriculography multiple-gated acquisition scan; NCCTG N9831, North Central Cancer Treatment Group; NRG1, neuregulin 1; NRTK, non-receptor tyrosine kinase; NSABP B-31, National Surgical Adjuvant Breast and Bowel Project; NYHA, New York Heart Association; PACS 04, Protocole Adjuvant dans le Cancer du Sein trial; PDGFR, plateled-derived growth factor receptor; PERK, ER-resident eukaryotic translation initiation factor 2α kinase; P13K, phosphatidylinositol 3-kinase; PKCδ, protein kinase Cδ; PTX, paclitaxel; RAF-1, serine/threonine-protein kinase-transforming protein; ROS, reactive oxygen species; SMR, standardised mortality rate; STAT, signal transducer and activator of transcription; SUDE, sunitinib-derived editor; TEACH, Tykerb Evaluation After Chemotherapy trial; TfR, transferrin receptor; TKI, tyrosine kinase inhibitor; TOP2A, topoisomerase II alpha; USO-9735, US Oncology 9735 study; VEGFR, vascular endothelial growth factor receptor; XeNA, Xeloda in Neoadjuvant trial. ⁎ Corresponding author. Department of Pharmacology, Via Irnerio, 48, I-40126 Bologna BO, Italy. Tel.: +39 051 2091805; fax: +39 051 248862. E-mail address: [email protected] (F. De Ponti). 0163-7258/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.pharmthera.2009.10.002

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4. Early detection and monitoring . . . 5. Perspectives and concluding remarks Acknowledgment . . . . . . . . . . . . References . . . . . . . . . . . . . . .

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1. Introduction 1.1. Background and aim In the past few decades, the radical change in life expectancy of people suffering from several forms of malignancy has sometimes led to optimistically label cancer as an easily manageable disease, similar to hypertension or diabetes. Indeed, the unquestionable clinical benefit in terms of disease-free survival should not cause underestimation of the safety profile of anticancer drugs. Actually, a number of blockbuster drugs used in oncology can affect the heart in several ways (Yeh et al., 2004; Jones & Ewer, 2006; Yeh, 2006; Menna et al., 2008; Yeh & Bickford, 2009). The term cardiotoxicity encompasses a number of heterogeneous side effects including arrhythmias (especially torsades de pointes induced by QT prolonging drugs), changes in blood pressure, myocardial ischemia, thrombosis or impairment in myocardial contraction and/or relaxation (i.e. systolic and diastolic dysfunction) (Table 1). Cardiovascular safety currently represents an open challenge both for drug regulators, before and after marketing authorization, and for physicians who face adverse drug reactions in clinical practice. From a regulatory standpoint, QT prolongation (mostly, but not exclusively, through hERG K+ channel blockade) is recognized as one of the most common causes of drug withdrawal/labelling changes in the past decade (De Ponti et al., 2000; De Ponti et al., 2002; Shah, 2006). Existing guidelines describe non-clinical screens to unmask the QT prolonging potential of novel products (ICH S7B Guideline, 2005b) and advise to conduct a detailed investigation on the QT liability of a compound (the so called “thorough QT study”) in the early phase of drug development (ICH E14 Guideline, 2005a). However, this topic will not be discussed here, because it has already been covered by a Special issue of this Journal (Hancox et al., 2008; Gintant, 2008; Shah, 2008) and by a number of extensive reviews (Recanatini et al., 2005; Strevel et al., 2007; Morganroth, 2007; Curigliano et al., 2008; Raschi et al., 2008; Sarapa & Britto, 2008; Rock et al., 2009). Anticancer drug-induced myocardial dysfunction [especially, decreased left ventricular ejection fraction (LVEF) resulting in congestive heart failure (CHF)] is a rapidly evolving field and is the focus of the present review. For several decades, the problem was almost exclusively associated with anthracyclines, for which cumulative dose-related cardiac damage was the use-limiting step (Minotti et al., 2004). 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. The aim of this review is twofold: 1) to provide an insight into putative molecular mechanisms involved in chemotherapy-induced cardiotoxicity; 2) to address the key issues to reduce cardiotoxicity in the clinical setting, highlighting unanswered questions on monitoring and predicting this risk in cancer survivors. In this perspective, the precise identification of the antitarget (i.e. the unwanted target causing

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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. 1.2. Impact of the problem for patients, clinicians and drug developers Cardiotoxicity may occur during or shortly after treatment, within days or weeks after anticancer treatment, or may not be apparent until months, and sometimes years, after completion of chemotherapy. The extensive use of chemotherapeutics in the clinical setting has raised concern on the long-term cardiovascular side effects among cancer survivors. Unfortunately, there is no consensus on the approach to monitor myocardial function in these patients and no predictive models have been developed to estimate this risk. Current investigations focus on new “targeted drugs”, for which cardiotoxicity was not predicted on the basis of pre-clinical evidence (e.g. trastuzumab). Moreover, the higher than expected incidence of cardiac dysfunction in patients undertaking combination regimens adds a further dimension to the complexity of the scenario. Since the molecular bases are still far from being elucidated, the joint effort of toxicologists and drug developers is needed to identify the antitarget (i.e. the target causing side effects). This topic is of particular concern for new tyrosine kinase inhibitors, such as imatinib, because preclinical models and clinical trials do not necessarily reflect what happens in clinical practice. Moreover, the issue of long-term cardiac effects and reversibility of damage is unresolved. The large number of cancer survivors [∼ 270,000 in the USA (Oeffinger et al., 2006)] has prompted studies on the long-term outcomes associated with chemotherapy: health status, mortality, and morbidity (Hudson et al., 2003; Oeffinger et al., 2004; Robison, 2005; Robison et al., 2005). As regards anthracyclines, a vast amount of literature exists. In a retrospective analysis of 20,227 5-year cancer survivors, Mertens et al. (2008) found a statistically significant excess standardised mortality rate (SMR = 8.2) of death from cardiac causes. A similar study in a large Nordic cohort documented a SMR of 5.8 for cardiac death and 3.9 for sudden, presumed cardiac, deaths (Moller et al., 2001). Moreover, results from the Childhood Cancer Survivor Study (CCSS) showed that 30 years after treatment, the relative risk of congestive heart failure was 15-fold higher than controls (Oeffinger et al., 2006). A population-based study of breast cancer survivors showed that women aged 66 to 70 years who received anthracyclines and had a more than 10-year follow-up experienced higher rates of CHF than did women who received neither anthracyclines nor chemotherapy (Pinder et al., 2007). This wealth of data indicated that cardiotoxicity associated with anthracyclines is irreversible, progressive and cumulatively dose-dependent (the so called type I cardiotoxicity) as compared to that of trastuzumab (Ewer & Lippman, 2005). So far, several risk factors for heart failure have been identified and some of these, including cumulative dose, dose rate, dosing schedule, and concomitant treatment, are potentially modifiable (Lipshultz et al., 2008). Although this knowledge may allow clinicians to tailor management at the individual level, the main concern with anthracycline-related cardiac damage pertains to the paradox that some low-risk patients may develop cardiotoxicity and not all highrisk patients may experience cardiac failure (Carver et al., 2007). Concerning targeted therapy, the actual magnitude of the problem is at present unclear because only in a few cases (e.g. trastuzumab and lapatinib) has prospective evaluation of cardiac function been performed.

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The major point that should be clarified regards the uncertainty surrounding definition and assessment of cardiotoxicity (Ewer & Lenihan, 2008). Despite universal adoption, LVEF does not represent the flawless method to evaluate cardiac functional reserve: because of its inherent subjectivity in the interpretation of LVEF as assessed by echocardiography (ECHO), a drop in this parameter does not always reflect cardiac injury. Moreover, there are different approaches in monitoring LVEF among trials: as an example, some consider a single LVEF drop, whereas others consider as significant an absolute decline of at least 10 percentage points from baseline. Given the inconclusive evidence from clinical experience, a step back to basic science is advisable. First, the predictivity of pre-clinical models should be clarified in order to screen for cardiotoxicity during the early phases of drug development. Insights into relevant molecular mechanisms involved in the pathophysiology of CHF may pave the way to expand therapeutic options of physicians. Moreover, lessons and experience gained from approved kinase inhibitors encourage toxicologists to identify antitargets causing cardiotoxicity and turn promiscuous drugs into safer agents (Zhang et al., 2008). 2. Anthracycline-induced cardiotoxicity Anthracyclines such as doxorubicin (DOX), epirubicin (EPI), and daunorubicin (DNR) remain among the most active anticancer agents for treatment of a wide variety of solid tumors and hematological malignancies. Unfortunately, the public concern surrounding anthracycline-induced cardiotoxicity (i.e. cardiomyopathy and congestive heart failure) still limits their usefulness. Despite more than 40 years of investigation, the pathogenic mechanisms responsible for cumulative dose-dependent anthracycline cardiotoxicity have not been fully elucidated.

Von Hoff et al. (1979) firstly estimated that the incidence of CHF was 3% at a cumulative DOXO dose of 400 mg/m2, increasing to 7% at 550 mg/m2 and to 18% at 700 mg/m2. Further retrospective investigation of three prospective studies (Swain et al., 2003) identified a higher incidence at a lower dose (5% at 400 mg/m2 and 26% at 550 mg/m2). A multivariate analysis (Krischer et al., 1997) found that patients who received N550 mg/m2 were five times more likely to experience early cardiotoxicity than those who received a lower cumulative doses. For EPI, Ryberg et al. (1998) reported a risk of CHF of 0.6%, 4.3% and 14.5% at cumulative dose of 550 mg/m2, 900 mg/m2 and 1000 mg/m2, respectively. For these reasons, the maximum recommended lifetime cumulative doses were 450 to 550 mg/m2 for DOXO and 900 mg/m2 for EPI (Wouters et al., 2005). In any case, there is no absolutely safe dose of anthracycline; even if lowering of the cumulative dose might appear to be a solution towards reducing cardiotoxicity, cardioprotection must be balanced with oncologic efficacy (Lipshultz & Colan, 2004). The rate of anthracycline administration has an effect on the relative risk of developing cardiotoxicity during or following treatment. Prolonged infusion therapy has been reported to reduce cardiac damage (Legha et al., 1982; Hortobagyi et al., 1989). Moreover, patients treated at a younger age appear to be more vulnerable to anthracycline induced cardiotoxicity. An age of b4 years at the time of exposure is associated with a significant risk factor to later cardiac dysfunction. Radiation therapy is frequently used in combination with chemotherapy and may worsen the cardiotoxic effects of anthracycline, but the available evidence is inconclusive. These modifying factors, indeed, may contribute to lower the threshold for the occurrence of cardiotoxicity [Fig. 1: this is the so-called “multiple-hit” hypothesis (Jones et al., 2007)]. 2.2. Mechanisms involved

2.1. Early and delayed cardiac events Anthracycline-induced cardiotoxicity is broadly classified into three categories: (1) acute, (2) early onset chronic progressive cardiomyopathy and (3) late onset chronic progressive cardiomyopathy (Giantris et al., 1998). They differ in time of onset, clinical characteristics, associated risk factors and molecular mechanisms. Acute anthracycline-induced cardiotoxicity is rare [occurring in b1% of childhood cancer patients (Giantris et al., 1998)], transient and independent of the dose. It is generally characterized by electrocardiographic changes including ST-T wave alterations and QT prolongation that may occur during or within several hours of the administration. These abnormalities are usually clinically silent and resolve when therapy is discontinued (Steinberg et al., 1987). However, this initial injury should be viewed as the harbinger of subsequent myocyte death, which later appears in its irreversible nature. Early-onset chronic progressive anthracycline-induced cardiotoxicity occurs within 1 year after anthracycline treatment. Adult patients may develop electrophysiological changes, left ventricular dysfunction, decreased exercise capacity and clinical heart failure. Late onset progressive cardiotoxicity is defined as a cardiomyopathy that occurs after a latency period of 1 or more years following completion of anthracycline therapy. With this type of cardiotoxicity, there is a period during which no left ventricular dysfunction or arrhythmia is detected; however, after this latent period, there is a progressive and rarely fatal deterioration in cardiac function. The degree and progression of anthracycline-related toxicity differ among individuals, suggesting that genetic predisposition and risk factors are involved, for example cumulative dose, dose rate, dosing schedule and concomitant treatment (Lipshultz et al., 2008). These risk factors relate to early and late, but not acute cardiotoxicity. A high cumulative anthracycline dose is a well recognized risk factor for cardiac damage and is currently the best predictor of cardiotoxicity:

Several mechanisms have been suggested to explain the pathogenesis of anthracycline-induced cardiotoxicity. The chemical structure of anthracyclines is complex (Fig. 2): these drugs are composed of an aglycone and a sugar. The aglycone consists of a tetracyclic ring with adjacent quinone-hydroquinone moieties and a short side chain with a carbonyl group at C-13 and a primary alcohol at C-14; the sugar is an amino-substituted trideoxy fucosyl moiety attached by a glycosidic bond to C-7 of ring A. The presence of a quinone moiety in the anthracycline ring structure has substantial clinical importance because of its involvement in both reductive and oxidative biotransformation, which ultimately generates highly reactive chemical species thought to be responsible for cardiotoxicity (Menna et al., 2007b). One electron addition to the quinone moiety of DOX, catalyzed by reductases located primarily to the mitochondrion, results in the formation of a semiquinone, which quickly regenerates its parent quinone by reducing molecular oxygen to superoxide anion (OU2−) and hydrogen peroxide (H2O2), members of the family of reactive oxygen species (ROS). Two-electron reduction of the side chain carbonyl group, catalyzed by a heterogeneous family of cytoplasmic aldehyde and carbonyl reductases, generates a secondary alcohol metabolite, doxorubicinol (DOXOL). Finally, disproportionation of the semiquinone may be accompanied by the reductive cleavage of the glycosidic bond and the concomitant reduction of the side chain carbonyl group, yielding an aglyconic secondary alcohol (7-deoxydoxorubicinolone) (Fig. 2). Oxidative stress, ion dysregulation, and alterations of the cardiacspecific gene expression program cooperate at inducing cardiomyopathy. It is also hypothesized that ROS and secondary alcohol metabolites might have separate roles. The high reactivity of ROS against cell constituents and the lack of effect of antioxidants against chronic cardiomyopathy suggest a role of ROS confined to acute cardiac dysfunction; in contrast, the pharmacokinetics and the pharmacodynamics of secondary alcohol metabolites suggest a key role in

Table 1 Cardiovascular toxicities associated with anticancer drugs. Cardiac toxicities with relative frequencya

Mechanism(s)

Sections covering cardiac safetya

Other common or clinically important toxicitiesa

Various neoplastic disorders

Acute cardiotoxicity (transient arrhythmias, especially sinus tachycardia with QT prolongation): reported CHF (early and delayed onset) DOXO: 0.14–18% (400–700 mg/m2) LDOXO: 3–11% (higher risk for cumulative dose N 550 mg/m2) EPI: 0.9–3.3% (550–900 mg/m2)

Oxidative stress (ROS) Iron chelation

Boxed warning (CHF) Warnings and precautions Adverse reactions

Gastrointestinal toxicity Myelotoxicity Local toxicity (extravasation)

Multiple sclerosis Acute myeloid leukemia Various solid tumors

CHF: 2.6% (cumulative dose of 140 mg/m2) Bradyarrhythmia: reported

Oxidative stress (different from anthracyclines)

Boxed warning (CHF) Warnings and precautions Adverse reactions

Neurotoxicity (for intrathecal administration) Myelotoxicity

Alkylating agents Cisplatin

Various neoplastic disorders

Electrolyte imbalance (hypomagnesaemia) Coronary artery fibrosis?

Adverse reactions

Myelotoxicity Nephrotoxicity Ototoxicity Gastrointestinal toxicity Neurotoxicity (peripheral neuropathy)

Cyclophosphamide

Various neoplastic disorders

Thromboembolic disorders: 12.9% CHF: 5.1% Hypertension: reported Orthostatic hypotension: reported Myocardial ischemia/infarction: reported Bradyarrhythmia: reported CHF: 8–27% (various combinations) Hemorrhagic myo-pericarditis: reported

Endothelial capillary damage

Warnings and precautions Adverse reactions

Ifosfamide

Various neoplastic disorders

Arrhythmias (including premature atrial contractions, premature ventricular contractions, supraventricular tachycardia, atrial fibrillation, atrial flutter): 15% (supraventricular tachyarrhythmia) CHF: 8% to 67% (dose 10–18 g/m2)

Loss of striation, fragmentation of ventricular muscle fibers?

Adverse reactions

Mitomycin

Various solid tumors

CHF: reported Edema: reported Thrombophlebitis: reported

Oxidative stress

Adverse reactions

Busulfan

Leukemias

Edema: 79% Tachyarrhthmia: 44% Hypertension (all grade): 36% Vasodilation: 25% Hypotension (all grade): 11% Cardiac tamponade: 2% Left heart failure: 2% Complete A–V block: 2% Endomyocardial fibrosis: reported

Unknown

Adverse reactions

Pulmonary toxicity (pulmonary fibrosis and interstitial pneumonitis) Gastrointestinal toxicity Nephrotoxicity (hemorrhagic cystitis) Skin toxicity (alopecia) Gastrointestinal toxicity Myelotoxicity Neurotoxicity Myelotoxicity Nephrotoxicity (renal dysfunction, Fanconi syndrome, hemorrhagic cystitis) Myelotoxicity Nephrotoxicity (hemolytic uremic syndrome) Pulmonary toxicity Gastrointestinal toxicity Myelotoxicity Neurotoxicity Gastrointestinal toxicity Pulmonary toxicity (rare but clinically significant) Endocrine toxicity (electrolyte imbalance)

Antimetabolites Capecitabine

Various solid tumors

CHF: reported Dysrhythmias: reported Myocardial ischemia/infarction: reported Sudden death: reported

Vasospasm

Warnings and precautions Adverse reactions

5-fluorouracil

Various solid tumors

Arrhythmia: 1.2–18% Myocardial ischemia/infarction: reported Sudden death: reported CHF: reported Thrombophlebitis: reported

Vasospasm, endothelial cell damage, interference with myocardial cell metabolism?

Adverse reactions

Anthracyclines DOXO EPI LDOXO

Anthraquinolones Mitoxantrone

(continued on next page)

199

Gastrointestinal toxicity Myelotoxicity Hepatotoxicity Skin toxicity (hand-and-foot syndrome) Neurotoxicity Myelotoxicity Skin toxicity (hand-and-foot syndrome) Gastrointestinal toxicity Neurotoxicity (rare but clinically significant peripheral neuropathy) Ocular toxicity

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Therapeutic use(s)

Drug class/example(s)

200

Table 1 (continued) Therapeutic use(s)

Cardiac toxicities with relative frequencya

Mechanism(s)

Sections covering cardiac safetya

Other common or clinically important toxicitiesa

Cytarabine

Leukemias

Pericarditis with effusion: rare (less than 0.1%) Vasculitis: reported

Hypersensitivity?

Warnings and precautions Adverse reactions

Fludarabine

B-cell chronic lymphocytic leukemia

Edema: 8–19% (peripheral edema 0–7%) Chest pain: 0–6%

Impaired cellular energy metabolism

Adverse reactions

Methotrexate

Various neoplastic disorders

Pericarditis: reported Pericardial effusion: reported Hypotension: reported Thrombolic events: reported Vasculitis: reported

Increased homocysteine concentration? Hypersensitivity?

Adverse reactions

Myelotoxicity Skin toxicity Gastrointestinal toxicity Neurotoxicity (cerebellar toxicity) Ocular toxicity Skin toxicity Neurotoxicity Pulmonary toxicity Autoimmune disorders (hemolytic anemia, thrombocytopenia/thrombocytopenic purpura, Evans syndrome) Gastrointestinal toxicity Nephrotoxicity Myelotoxicity Pulmonary toxicity Gastrointestinal toxicity Hepatotoxicity Neurotoxicity Nephrotoxicity

Antimicrotubules Taxanes (e.g. PTX, DTX)

Various neoplastic disorders

Edema: 47–64.1% (DTX) Vasodilation: 27% (DTX) Hypotension: 9–17% (PTX); 2.6% (DTX) CHF: PTX = 1% (alone), 13% (with trastuzumab); DTX = 2.3% Bradyarrhythmia: 3% Syncope: 1.6% (DTX) Phlebitis: 1.2% (DTX) A–V block: b 1% Supraventricular tachycardia: rare Myocardial ischemia/infarction: rare (PTX); 1.7% (DTX) Atrial fibrillation: rare Venous thrombosis: reported Myocardial ischemia/infarction: reported Hypertension: reported Raynaud's phenomenon: reported Cardiovascular autonomic neuropathy: reported Tachycardia: reported Orthostatic hypotension: reported

Hypersensitivity reaction

Warnings and precautions Adverse reactions

Skin toxicity (especially for DTX) Anaphylaxis Myelotoxicity Neurotoxicity (peripheral neuropathy) Gastrointestinal toxicity Hypersensitivity reactions Musculoskeletal toxicity (DTX)

Vasospasm?

Adverse reactions

Gastrointestinal toxicity Neurotoxicity (peripheral neuropathy) Pulmonary toxicity

Vinca alkaloids (e.g. vincristine, vinblastine)

Various neoplastic disorders

Topoisomerase inhibitors Etoposide

Various neoplastic disorders

Hypotension: 1–2% CHF: reported Myocardial ischemia/infarction: reported Chemical phlebitis: reported

Vasospasm

Warnings and precautions Adverse reactions

Gastrointestinal toxicity Myelotoxicity Anaphylactic reactions

Aromatase inhibitors Anastrozole

Breast cancer

Vasodilation: 25–36% Edema: 7–11% (peripheral edema: 5–10%) Chest pain: 5–7% Ischemic heart disease: 4% Hypertension: 2–13% Thrombophlebitis: 2–5% Angina: 2.3% Myocardial infarction: 1.2%

Unknown

Warnings and precautions Adverse reactions

Gastrointestinal toxicity Musculoskeletal toxicity Neurotoxicity (including psychiatric disorders) Reproductive toxicity

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Drug class/example(s)

Table 1 (continued) Drug class/example(s)

Therapeutic use(s)

Cardiac toxicities with relative frequencya

Biological agents (excluding monoclonal antibodies and tyrosine kinase inhibitors) IL-2 Metastatic melanoma Hypotension (Capillary leak syndrome): 71% Metastatic renal cell carcinoma Ventricular tachycardia: reported Coronary artery thrombosis: reported Myocarditis: reported

Mechanism(s)

Sections covering cardiac safetya

Other common or clinically important toxicitiesa

Unknown (autoimmune disorders?)

Boxed warnings (capillary leak syndrome) Contraindications Warnings and precautions Adverse reactions

Gastrointestinal toxicity Myelotoxicity Neurotoxicity Nephrotoxicity Pulmonary toxicity Autoimmune disorders exacerbation

Various neoplastic disorders

Hypertension: 11% Chest pain: 4–11% Hypotension: 4% Arrhythmias: b 3% Myocardial ischemia/infarction: rare

Unknown

Warnings and precautions Adverse reactions

Endocrine toxicity Autoimmune disorders exacerbation Myelotoxicity Neurotoxicity

Miscellanea Thalidomide

Various neoplastic disorders

Thromboembolic events: 22.5% Hypotension: 15.7% Edema: 4.2–56.9% Bradycardia: reported Orthostatic hypotension: reported

Unknown

Boxed warnings (thromboembolic events) Warnings and precautions (thromboembolic events) Adverse reactions

Bleomycin

Various neoplastic disorders

Likely related to oxidative stress

Adverse reactions

Pentostatin

Hairy cell leukemia

Unknown

Warnings and precautions (hypotension) Adverse reactions

Pulmonary toxicity Neurotoxicity Hepatotoxicity

Arsenic trioxide

Leukemias

Edema: 50% Raynaud's phenomenon: 37% Myocardial ischemia/infarction: unusual Arterial thrombosis: reported Cerebrovascular accidents: reported Angina pectoris, tachy/bradycardia, A–V block, cardiac arrest, extrasystoles, heart failure, hemorrhage, hyper/hypotension, pericardial effusion, pulmonary embolus, sinus arrest, thrombophlebitis and vasculitis: infrequent Edema with pericardial effusion (during acute promyelocytic leukemia differentiation syndrome): 40% QT prolongation and TdP: reported

Human birth defects Skin toxicity Endocrine toxicity Gastrointestinal toxicity Myelotoxicity Neurotoxicity Pulmonary toxicity (pulmonary fibrosis) Skin toxicity

Hypomagnesaemia Interference with hERG trafficking

Skin toxicity Gastrointestinal toxicity Myelotoxicity Neurotoxicity

All-trans retinoic acid

Skin disorders Acute promyelocytic leukemia

Boxed warnings (QT prolongation and TdPoccurrence) Warnings and precautions (QT prolongation and TdP occurrence) Adverse reactions Boxed warnings (acute promyelocytic leukemia differentiation syndrome) Warnings and precautions (acute promyelocytic leukemia differentiation syndrome) Adverse reactions

Tamoxifen

Breast cancer

Endocrine toxicity Reproductive toxicity

Bortezomib

Multiple myeloma Mantle cell lymphoma

Boxed warnings (thromboembolism) Contraindications (thromboembolism) Warnings and precautions Adverse reactions Warnings and precautions Adverse reactions

Pericardial effusion (during acute promyelocytic leukemia differentiation syndrome): 25% Arrhythmias: 23% Hypotension: 14% Hypertension: 11% Phlebitis: 11% CHF: 6% Thromboembolism: 1.7% Cerebrovascular accidents: 0.3% Myocardial infarction: reported Edema: reported CHF: 15% Hypotension: 12–15%

Unknown

Unknown

Inhibition of preoteasome activity and nuclear factor-kB?

Skin toxicity Gastrointestinal toxicity Myelotoxicity (mainly leukocitosis) Neurotoxicity

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Interferon-α2a

Gastrointestinal toxicity Myelotoxicity Musculoskeletal toxicity Neurotoxicity (peripheral neuropathy) Pulmonary toxicity

CHF: congestive heart failure; DOXO: doxorubicin; DTX: docetaxel; EPI: epirubicin; hERG: human ether a-go-go related gene; IL-2: interleukin 2; LDOXO: liposomal doxorubicin; PTX: paclitaxel; TdP: torsades de pointes. a Data from www.thomsonhc.com, DRUGDEX® Drug Summary Information. Last access 30/04/2009. 201

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Fig. 1. Effect of various modifying factors on the risk of cardiotoxicity. The cumulative doses indicated in the figure were obtained from the summaries of the product characteristics of marketed medicinal products.

Fig. 2. Reductive and oxidative pathways of anthracycline metabolism and their possible involvement in cardiotoxicity. One-electron reduction of the quinone moiety is accompanied by formation of ROS and 7-deoxydoxorubicinolone; two-electron reduction of the side chain carbonyl group generates the secondary alcohol metabolite DOXOL. This figure shows the molecular linkage between iron and anthracycline metabolism. DOX can bind to iron by forming DOX–iron(III) complexes, which may lead to ROS formation that deteriorates proteins, lipids and DNA. In addition, DOXOL and drug–iron complexes are active molecular mediators in the cellular IRP1 RNA binding activity and iron homeostasis but the mechanism involved remains controversial.

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promoting the progression of cardiotoxicity toward chronic dysfunction. Unlike acute cardiotoxicity, the delayed manifestation of anthracycline exposure often presents as clinical heart failure, is characterized by structural changes to the heart including a decrease in the thickness of left ventricular wall, reduced myocardial mass and reduced ventricular compliance. This complication is considered to be due to recurrent damage of cardiomyocytes and develops after completion of cumulative anthracycline regimens, usually within a year. The ultrastructural features seen in endomyocardial biopsies of patients with anthracycline-associated heart failure include the loss of myofibrils, dilation of the sarcoplasmic reticulum, cytoplasmic vacuolization, swelling of mitochondria, and increased number of lysosomes. Anthracycline-induced cardiotoxicity seems to involve myocyte cell death via multiple mechanisms, but there are conflicting data on the specific apoptotic pathway involved. Oxidative stress has been considered an important mechanism leading to myocyte death, but it is sufficient to induce myocyte death as well as activation of the so called “fetal gene program” that is a feature of many forms of heart failure. Moreover, because cardiomyocytes are ill-equipped with OU2− or H2O2-detoxifying enzymes like catalase or superoxide dismutase, the accumulated radicals eventually destroy the mitochondria (Chen et al., 2007). Cellular stress activates a host of kinase pathways that appear important in determining cell fate, and these pathways modulate the response of the heart to anthracycline exposure. Mitogen/Stress Activated Protein Kinase (MAPKs and SAPKs) seems to be cellular mediator linking anthracyclines to the apoptotic pathway. In the cardiac myocytes, extracellular signal-regulated kinase (ERK) is activated by growth factors/hypertrophic agents and thought to mediate cell survival. The SAPKs jun N-terminal kinase (JNK) and p38 are activated by cellular stress and correlate with cardiac myocyte apoptosis. Recent findings also suggest that ROS production can activate these pathways, in particular JNK and p38, supporting the association of anthracyclines and SAPK mediated apoptosis (Chen et al., 2007). Anthracycline-induced apoptosis in the heart appears to involve a mitochondrial pathway, including Bax, cytochrome c, and caspase-3. It is well established that once cytochrome c is released from the mitochondria into the cell, it interacts with Apaf-1 and procaspase-9, generating caspase-9, which in turn activates caspase-3, inducing DNA fragmentation and apoptosis. Recent studies have demonstrated release of cytochrome c after anthracycline treatment in a rat myocyte cell line (H9C2) and in vivo (Chen et al., 2007). It was also observed that increased Bax levels can lead to formation of multimers, destabilizing the mitochondria and inducing cytochrome c release. The involvement of caspase-3 is supported by the presence of activated caspase-3 in anthracycline-induced cardiomyopathy and ischemiareperfused rat hearts (Yaoita et al., 1998). The effects of anthracycline on cardiac cells that have been implicated in myocyte death may also induce other cellular phenotypes such as the disruption of cardiac sarcomeric structure. Since the integrity of the myocyte sarcomere is important for myocyte function its disorganization can lead to impaired cardiac function and cardiomyopathy. The mechanisms for this are incompletely understood, but appear to involve accelerated degradation of key sarcomeric proteins, such as titin, and disruption of new sarcomere protein synthesis via altering transcriptional regulation. The reductive metabolism of anthracyclines may be involved in the development of cardiac damage through an iron-dependent mechanism (Menna et al., 2007b). Under physiological conditions, the intracellular iron levels are regulated through a coordinate regulation of ferritin and transferrin receptor (TfR, the main iron uptake protein). The levels of ferritin and TfR are governed at a transcriptional level by two proteins called Iron Regulatory Protein 1 (IRP-1) and Iron Regulatory Protein 2 (IRP-2). The first mechanism that links iron and anthracycline metabolism involves the two products of the redox cycling of the quinone moiety, the semiquinone free radical and OU2−;

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they have a one-electron redox potential that is low enough to reduce Fe(III) and release Fe(II) from ferritin. In addition, DOXO can directly bind iron and, in the presence of oxygen, can cycle between the iron (II) and iron(III) states. The DOXO–iron(III) complex can be reduced to the DOXO–iron(II) complex in the presence of reducing agents such as NADPH cytochrome P450 reductase, glutathione, and cysteine. Drug–iron complexes increase the cellular levels of ROS, and eventually induce OU2−/H2O2 to produce hydroxyl radicals (UOH) or iron– peroxo complexes that deteriorate proteins, lipids and DNA (Fig. 2). Furthermore, it is clear that DOX affects cellular IRP1-RNA-binding activity and iron homeostasis but it is controversial whether intracellular formation of DOXOL, the DOX–iron(III) complex, or both are active molecular effectors. The RNA binding activity of these compounds regulates synthesis of TfR 1 and ferritin, which are crucial proteins involved in iron uptake and storage, respectively. In addition, DOX prevents the mobilization of iron from ferritin by a mechanism that may involve lysosomal degradation of this protein. Prevention of iron mobilization from ferritin would probably interfere with cellular function because of the importance of iron for DNA synthesis and energy metabolism (Xu et al., 2005). Iron-independent actions have also been described and now challenge the role of oxidative stress as the key mechanism of anthracycline cardiotoxicity (Gianni et al., 2008). 7-Deoxydoxorubicinol modifies the geometry and permeability of the mitochondria, inducing a collapse of the transmembrane potential and the loss of pyridine nucleotides and calcium (Menna et al., 2007b). Moreover, secondary alcohol metabolites are several-fold more potent than their parent anthracyclines in inactivating the Ca2+/Mg2+-ATPase of sarcoplasmic reticulum and the Na+/K+-ATPase and Na+/Ca2+ exchanger of sarcolemma; thus, DOXOL has many negative effects on energy metabolism and ion gradients. Secondary alcohol metabolites are also more potent than the anthracyclines at inhibiting Ca2+ release from sarcoplasmic reticulum and contribute to suppressing the expression of the Ca2+-gated Ca2+ release channel of sarcoplasmic reticulum. 2.3. Association therapy: anthracyclines and taxanes The anthracycline, DOXO, and the taxanes, paclitaxel (PTX) or docetaxel (DTX), are highly active antitumor drugs. The DOXO–PTX combination was shown to induce high response rates in women with metastatic breast cancer, particularly when the two drugs were administered almost concomitantly. DOX and PTX exhibit different mechanisms of action (DNA intercalation/topoisomerase II inhibition vs. microtubule stabilization), non-overlapping toxicities (cardiomyopathy vs. neuropathy), and incomplete cross-resistance; PTX has been known to induce arrhythmias or blood pressure disorders, effects caused by the PTX vehicle Cremophor EL. Combining DOXO and PTX offers a therapeutic opportunity to improve treatment of breast cancer; however, the clinical use of DOXO-PTX combinations is limited by a higher incidence of the cardiac toxicity known to be induced by DOXO. Pivotal trials have shown that DOX immediately followed by PTX causes cardiomyopathy and congestive heart failure (CHF) in ∼19% of patients exposed to 420–480 mg of DOX/m2, as if PTX accelerated the dose-related progression of anthracycline cardiotoxicity (Gianni et al., 1995, 1997). Subsequent pharmacokinetic studies revealed that, compared with DOX alone, the DOX-PTX combination led to a ∼30% increase of the plasma area under curve (AUC) of DOX and more than doubled the AUC of DOXOL, a secondary alcohol metabolite (Menna et al., 2007a). The effect of PTX on the plasma exposure to DOXOL was attributed to interferences of the PTX vehicle, Cremophore EL, with the biliary P glycoprotein-mediated elimination of the anthracycline molecule. This pharmacokinetic factor cannot be invoked to explain the cardiotoxic synergism of PTX with DOX, as DOXOL is too polar for partitioning from the extracellular fluid into cardiomyocytes. Studies with translational models of human heart showed that PTX acted as an allosteric modulator of the cytoplasmic

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aldehyde reductases that formed DOXOL by adding two electrons to the side chain carbonyl group of DOX; this resulted in a reduced Km value and increased Vmax value for the reaction of DOX with such reductases, leading to an improvement of the catalytic efficiency (Vmax/Km) with which the human myocardium generated DOXOL. Based upon these findings (Salvatorelli et al., 2006b) developed a kinetic and allosteric model showing stimulation or inhibition of DOXOL formation induced by low or high concentrations of PTX. According to this model, low concentrations of PTX bound with high affinity to an allosteric site of aldehyde reductases and favored the conformational changes that induced the conversion of DOX to DOXOL, while high concentrations of PTX reduced DOXOL formation by binding with low affinity to the catalytic site and displacing DOX. Currently, the increase of cardiotoxicity of DOX–PTX is prevented by limiting the cumulative dose of DOX to 360 mg/m2 or by separating DOX and PTX by intervals of more than 4 h. On the basis of the cellular pharmacokinetics of secondary alcohol metabolites, the therapeutic association discussed above represents the best known example of a toxic synergism between anthracycline and other chemotherapeutic drugs that caused little or no cardiotoxicity per se. 2.4. Current options to reduce anthracycline cardiotoxicity 2.4.1. Treating cardiac dysfunction Clinical practice guidelines for treating patients with asymptomatic left ventricular dysfunction or CHF include a combination of agents: β-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptors blockers, with the addition of diuretics, aldosterone antagonists, digoxin, nitrates or hydralazine after the onset of symptoms of heart failure. Comprehensive studies have not been conducted to demonstrate how these treatments could prevent the progression of cardiomyopathy in patients who received anthracyclines and little, if any, is known on long-term therapeutic benefits (Lipshultz et al., 2002; Lipshultz & Colan, 2004; Silber et al., 2004). The indirect role of growth hormone (GH) on the heart prompted a number of studies in survivors of childhood cancer. However, several randomized trials failed to reveal clinical benefits of GH treatment, despite increase in ventricular mass (Lipshultz et al., 2005). 2.4.2. Preventing cardiac dysfunction The need to reduce anthracycline cardiotoxicity in clinical practice encourages the development of cardioprotective strategies retaining antitumor activity. Although no absolute safe dose exists, dose limitation has been adopted by most clinical protocols as a feasible approach (Wouters et al., 2005). Schedule modification (i.e. converting bolus administration into slow prolonged infusion) has been reported to be less cardiotoxic (Legha et al., 1982; Hortobagyi et al., 1989), but still remains a controversial approach: there is no definite evidence suggesting a benefit in response rate and overall survival (van Dalen et al., 2006b). A more recent approach consists of entrapping anthracyclines in uncoated or pegylated liposomes. Liposome encapsulation alters the pharmacokinetics and biodistribution profile of anthracyclines. Following administration of a liposomal formulation, most of the DOXO in plasma is encapsulated. Once in the tissue, encapsulated DOXO is released from the liposome. Due to their size (100–180 nm in diameter), liposomes are too big to cross the normal endothelium in the heart, but diffuse through the leaky vasculature of tumors. Thus, with a liposomal product, the drug is preferentially directed away from sites of toxicity to the site of action. Liposome-encapsulated anthracyclines are also characterized by (i) reduced volume of distribution and clearance and prolonged half-life; (ii) limited conversion to aglycones or secondary alcohol metabolites; (iii) prolonged release of the drug within the tumor environment; (iv) limited ac-

cumulation in healthy tissues (like the heart) with a normal endothelial barrier (Minotti et al., 2004). Several modifications of the anthracycline basic structure have been performed to improve the therapeutic and pharmacological properties of the natural compound. A very instructive example is offered by EPI that differs from DOX in an axial-to-equatorial epimerization of the hydroxyl group at C-4′ in daunosamine. EPI seems to be a much better substrate than DOX for human liver UDP-glucuronosyltransferase 2B7; this minor difference facilitates the formation of glucuronides that are excreted in bile and urine. Improved glucuronidation and body clearance alter the dose-related antiproliferative activity of EPI, as shown by the fact that the dose of EPI equimyelotoxic to 1 mg of DOX is 1.5 mg. Recent studies with isolated murine cardiomyocytes or thin strips of human myocardium showed that EPI was similar to DOX in its partitioning from the extracellular fluid into the cells, but exhibited remarkable differences in terms of intracellular distribution. DOX entered the cytoplasm and then distributed to mitochondria, while EPI underwent sequestration in cytoplasmic acidic organelles and failed to produce mitochondrial levels high enough to create ROS (Salvatorelli et al., 2006a). Moreover, EPI showed an impaired catalytic efficiency for the same aldehyde reductases that converted DOX to DOXOL, such that epirubicinol (EPIOL) formation was ∼40% lower than that of DOXOL. The defective conversion to ROS and secondary alcohol metabolites should render EPI a better partner than DOX for combinations with drugs that aggravated cardiotoxicity. Further investigations showed that EPI in combination with PTX failed to stimulate EPIOL formation, presumably because its affinity for aldehyde reductases was low enough to prevent formation of ternary complexes (Salvatorelli et al., 2007). Recently, a more complex picture was hypothesized (Salvatorelli et al., 2009) to explain the reason why the gain in cardiac tolerability of EPI is lower than predicted on the basis of its defective conversion to toxic metabolites as discussed above. Indeed, the cardiac safety of EPI is probably limited by its higher (as compared to DOXO) accumulation in the heart (this accumulation may be even higher in the absence of doxorubicinolone, the product of EPI deglycosidation and carbonyl reduction). The hypothesis that differential accumulation of undegraded anthracyclines might induce cardiotoxicity by mechanisms independent of ROS and oxidative stress has important implications for the development of less cardiotoxic compounds (Menna et al., 2009). As reported above, anthracyclines markedly interfere with intracellular iron metabolism, which seems to play an important role in cardiotoxicity. The iron chelator, dexrazoxane, approved in 2002 by the US Food and Drug Administration (FDA), is a cardioprotective agent used in this setting. It is a bis-ketopiperazine, which permeates the cell membrane and can be rapidly hydrolyzed to its metal ion-binding metabolite, thus decreasing anthracycline-iron binding and ROS formation. Therefore, it indirectly inactivates free radicals attenuating their formation through intracellular iron chelation (Hasinoff & Herman, 2007). Unfortunately, a clinical trial suggested its possible interference with antitumor activity (Swain et al., 1997) and this observation still limits the use of dexrazoxane, in spite of the evidence for its cardioprotective efficacy (Swain & Vici, 2004). Another important caveat is that dexrazoxane, because of its pharmacodynamic properties, has probably only a marginal if any effect on iron-independent mechanisms mediating anthracycline-induced cardiotoxicity. A recent systematic Cochrane review (van Dalen et al., 2008) and the updated clinical guidelines of the American Society of Clinical Oncology (ASCO) conclude that despite a clear cardioprotective effect of dexrazoxane, it is not routinely used because of its potential interference with anti-tumor efficacy. The authors suggested considering its use in metastatic breast cancer and other malignancies, for patients who have received more than 300 mg/m2 DOXO who may benefit from continued DOXO-containing therapy, providing that cardiac monitoring is ensured (Hensley et al., 2009). Clinical trials are needed to evaluate the efficacy of dexrazoxane in hematological malignancies as well as adjuvant treatment of breast

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cancer. Its use in the pediatric setting and in the management of elderly patients with cardiac comorbidity also requires investigation. There is also interest in the use of dexrazoxane as an antidote for anthracycline extravasation (Kane et al., 2008). Recent findings suggest a potential role of endocannabinoid system inhibition in the protection against DOXO cardiotoxicity. Mukhopadhyay et al. (2007) reported that administration of CB1 receptor antagonists rimonabant or AM281 protected against the cardiotoxicity induced 5 days after treatment with a single high dose of DOXO. This observation has important implications for the development of new strategies for the protection against anthracycline-induced cardiotoxicity (Fajardo & Bernstein, 2007). Based upon these data, the concomitant use of anthracyclines and trastuzumab was initially abandoned in metastatic breast cancer patients, but is presently being reconsidered with less cardiotoxic preparations. 3. Cardiotoxicity of targeted drugs: the heart as an antitarget Targeted drugs (i.e. compounds acting through inhibition of a specific target molecule) represent the current mainstay in the treatment of several forms of cancer. Given the critical role in cell signal transduction, protein kinases have been exploited as attracting targets for anticancer therapy. Clinical practice relies on two main classes of drugs targeting tyrosine kinase receptors for growth factors: monoclonal antibodies and small molecule tyrosine kinase inhibitors (now referred to as TKIs). The era of targeted therapy began, respectively, with the FDA approval of trastuzumab for treatment of metastatic breast cancer (1998), and imatinib for chronic myeloid leukemia (2001). Despite recognized efficacy, their use is hampered by cardiac side effects (Table 2). In general, knowledge of the molecular basis underlying cardiotoxicity of targeted drugs depends on the discovery of (a) the specific target mediating cardiac damage and (b) the key signalling pathways involved in its pathogenesis (Force et al., 2007). Investigators distinguish between the so called “on target” and “off target” toxicity (Chen et al., 2008; Force & Kerkela, 2008). The on target effect is caused by a target promoting both cancer cell growth and cardiomyocyte function. The off target effect, instead, occurs when a TKI causes an inhibition of a “bystander” target (i.e. a target not essential to kill cancer cells but involved in cardiomyocyte survival). In general terms, the view that the heart is an antitarget should guide basic investigations in rational drug development. The type of approach depends both on the selectivity of the drug and on the localization/ function of the antitarget. The first situation arises when the drug is highly selective (i.e. it acts on a specific target), but target and antitarget coincide (i.e. the drug target is ubiquitarian). In this case, a realistic attempt could consist of acting on the delivery drug process (e.g. by using carriers/vehicles) in order to prevent cardiac accumulation (pharmacokinetic approach). The second (pharmacodynamic approach) is possible when target and antitarget do not coincide but are both affected by the scarce selectivity of the drug. A rational drug redesign is advisable to avoid cardiac injury while maintaining antitumor activity (pharmacodynamic approach) (Fernandez et al., 2007b; Crespo et al., 2008; Zhang et al., 2008). Recently, Fernandez and Sessel (2009) proposed, at a conceptual level, “therapeutic editing” to reduce side effects. The editor is defined as a drug capable of exerting selective antagonism in “off target” cells (i.e. myocytes), thus suppressing the adverse effect caused by the primary drug. Both editor and primary drug overlap in “on target” cells (i.e. tumor cells), thus acting synergistically. The clinical relevance of this approach remains to be established. 3.1. Trastuzumab Trastuzumab (Herceptin®) is a humanized monoclonal antibody targeted against the extracellular domain of the human epidermal growth factor receptor 2 (HER2, also known as ERBB2). Amplification

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of the HER2/neu gene and overexpression of the receptor occur in around 15–25% of women with early breast cancer, and are associated with an aggressive disease course and a poor prognosis, with high risk of recurrence and metastasis. The overwhelming benefits of trastuzumab for women with HER2-positive early and metastatic breast cancer, in terms of disease-free survival or overall survival, have been clearly demonstrated by several systematic reviews of adjuvant/ neoadjuvant trials (Viani et al., 2007; Rayson et al., 2008; Madarnas et al., 2008; Dahabreh et al., 2008; Bria et al., 2008; Untch et al., 2008; Nielsen et al., 2009; Mackey et al., 2009). Landmark adjuvant studies demonstrated that trastuzumab, either alone and in combination with chemotherapy, reduced the risk of death by 33% in women with HER2-positive early breast cancer (Piccart-Gebhart et al., 2005; Romond et al., 2005; Joensuu et al., 2006; Smith et al., 2007). Moreover, a cumulative analysis of major adjuvant trials showed that trastuzumab reduced the 3-year risk of occurrence of breast cancer by about one-half (Baselga et al., 2006). However, a higher than expected incidence of cardiac dysfunction was detected among patients receiving trastuzumab in combination with anthracycline-based therapy (Slamon et al., 2001). 3.1.1. Evidence-based cardiotoxicity of trastuzumab Although pre-clinical studies did not reveal any cardiac toxicity ascribable to trastuzumab, the first phase III pivotal trial demonstrated significant cardiac dysfunction (Slamon et al., 2001). Moreover, retrospective evaluation of seven phase II and phase III trials by the independent Cardiac Review and Evaluation Committee (CREC) documented this association identifying 112 patients (9.2%) with cardiac dysfunction. Predefined criteria were used for the diagnosis, and the New York Heart Association (NYHA) functional classification system was used to grade cardiotoxicity severity. The incidence of cardiac dysfunction varied from 1% to 27% in different arms of these trials and was higher in patients receiving concurrently anthracyclines (Seidman et al., 2002). Based upon these data, the concomitant use of anthracyclines and trastuzumab was abandoned in metastatic breast cancer patients. As a result, subsequent trastuzumab adjuvant trials were designed to include prospective evaluations of cardiac effects and protocols for cardiac monitoring and management. To date, HERA (Herceptin Adjuvant trial), NSABP B-31 (National Surgical Adjuvant Breast and Bowel Project), NCCTG N9831 (North Central Cancer Treatment Group), BCIRG 006 (Breast Cancer International Research Group) and FinHer (Finland Herceptin trial) represented five major randomized trials investigating various adjuvant approaches with trastuzumab. Data mining and across-trial comparisons are challenging and somewhat controversial because of differences in patient populations, chemotherapy regimens, monitoring schedules and sequencing of treatments. Each study used different entry criteria for cardiac function and cardiovascular risk, different definitions of cardiac dysfunction and different parameters to assess cardiac safety. Although it should be acknowledged that the overall incidence of cardiotoxicity was lower than that reported in the pivotal trial, this risk was increased in the trastuzumab arms compared with controls (except for the number of cardiac deaths). A recent meta-analysis of these trials revealed an absolute difference of 1.6% in occurrence of CHF between the trastuzumab and the non-trastuzumab arm, which implies that the number needed to harm is 62 (Bria et al., 2008). Among different trastuzumab-containing regimens, the incidence of CHF ranged from 0.4% (BCIRG 006) to 4.1% (NSABP B-31). The rate of significant LVEF drop (usually ≥10%) was 3–18% (HERA and BCIRG 006 respectively). A synopsis of available information concerning cardiotoxicity in adjuvant trials is provided in Table 3. The results from BCIRG 006, ECOG E2198 (Eastern Cooperative Oncology Group) and PASC 04 (Protocole Adjuvant dans le Cancer du Sein) trials have not yet been published. The ECOG E2198 trial (Sledge et al., 2006), a randomized phase II pilot trial involving 234 patients, was designed to examine cardiac

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Table 2 Kinase-targeting drugs associated with documented or supposed cardiac dysfunction(s) approved by the FDA. Agent

Class Molecular target(s)a

Therapeutic indication(s)

Drugs with a reported risk Imatinib TKI ABL1/2, PDGFRα/β, CML, Ph+ B-ALL, CMML, CEL, c-KIT GIST

Dasatinib

TKI

ABL1/2, PDGFRα/β, Resistant CML and Ph+ B-ALL c-KIT, NRTK (Src family)

Nilotinib

TKI

ABL1/2, PDGFRα/β, Resistant CML c-KIT

Sunitinib

TKI

VEGFR1/2/, c-KIT, PDGFRα/β, RET, CSF-1R, FLT3

Sorafenib

TKI

RAF, VEGFR2/3, PDGFRα/β, c-KIT, FLT3

MRCC, resistant GIST

Resistant RCC, unresectable HCC

Trastuzumab

mAb

HER2 (ERBB2)

HER2 positive breast cancer

Bevacizumab

mAb

VEGFR

Metastatic colorectal cancer, NSCLC, metastatic HER2 negative breast cancer

Drugs with an uncertain risk Lapatinib TKI HER2 (ERBB2) EGFR (ERBB1) Cetuximab

Metastatic HER2 positive breast cancer

mAb

EGFR (ERBB1)

Panitumumab mAb

EGFR (ERBB1)

Metastatic colorectal cancer, head and neck cancer Colorectal cancer

Rituximab

mAb

CD20

BL

Alemtuzumab mAb

CD52

Resistant B-CLL

Temsirolimus

TKI

mTOR

MRCC

Gefitinib Erlotinib

TKI TKI

EGFR (ERBB1) EGFR (ERBB1)

NSCLC NSCLC, PC

Cardiotoxicitiesb

Edema: 1.1–86.1% Chest pain: 7–11% CHF: 0.1–1% Tachycardia: 0.1–1% Cardiac tamponade: reported Fluid retention, all grades; 24–37% Dysrhythmias: 1–10% Chest pain: 1–10% CHF, all grades: 2% Generalized edema, all grades: 3% Superficial edema, all grades: 14–20% Pericardial effusion: 1–4% QT prolongation: reported QT prolongation: 1–10% SD: 0.6% Peripheral edema: 11% LVD: 11% (GIST) – 21% (MRCC) Hypertension: 15% (GIST) – 30% (MRCC) Peripheral edema: 11% (MRCC) QT prolongation/TdP: b0.1% Thrombosis: 3% (GIST) – 1% (MRCC) CHF: 0.1–1% Dysrhythmias: 0.1–1% Cardiac ischemia/infarction: 2.7–2.9% (HCC) Hypertension: 9–17% Thromboembolism: 0.1–1% CHF: 2–28% (see Table 3 for details) Peripheral edema: 5–10% Tachycardia: 5% (monotherapy) Thrombosis: 2.1–3.7% (adjuvant therapy) Hemorrhagic events: 2.3–32% Arterial thromboembolism: 8.5% Venous thromboembolism: 5–15.1% CHF/LVD: 1.7–2.2% Hypertension, all grade: 8–34%

LVD: 1.3–2% QT prolongation: reported Variant angina: reported Cardiopulmonary arrest/SD: 2% Myocardial infarction/shock: reported Peripheral edema: 12% Thrombophlebitis: 5% Venous thrombosis: reported Hypotension: 10% Arrhythmias, mostly supraventricular tachycardia: reported Vasculitis: reported Arrhythmias, primarily tachycardia: 10% Hypertension, all grade: 14% Hypotension: 16% Angina, all grade: 16% Edema, all grade: 35% Hypertension: 7% Venous thromboembolism: 2% Peripheral edema: 2% Venous thrombosis: 3.9% Myocardial infarction/ischemia: 2.3% Cerebrovascular accidents: 2.3%

Potential antitarget(s)

Mechanism(s)

ABL, PDGFR? Indirect mitochondrial dysfuntion

ABL, PDGFR? Indirect mitochondrial dysfuntion

hERG hERG hERG?

Delayed ventricular repolarisation Delayed ventricular repolarisation

PDGFR? VEGFR

Indirect mitochondrial dysfuntion Decreased NOS production

Delayed ventricular repolarisation hERG Decreased NOS/PGI2 production VEGFR RAF, PDGFR? Direct mitochondrial dysfunction

VEGFR VEGFR HER2

Decreased NOS production Decreased NOS/PGI2 production Indirect mitochondrial dysfunction

VEGFR

Decreased NOS/PGI2 production

VEGFR

Decreased NOS production

HER2? hERG

Delayed ventricular repolarisation

Molecular antitargets, mechanisms and actual risk are unkwownc

B-CLL: B-cell chronic lymphocytic leukemia; BL: B-cell lymphoma; CEL: chronic eosinophilic leukemia; CHF: congestive heart failure; CML: chronic myeloid leukemia; CMML: chronic myelomonocytic leukemia; FDA: Food and Drug Administration; GIST: gastrointestinal stromal tumor; HCC: hepatocellular carcinoma; LVD: left ventricular dysfunction; mAb: monoclonal antibody; MRCC: metastatic renal-cell carcinoma; NSCLC: non-small-cell lung cancer; PC: pancreatic cancer; Ph+ B-ALL: Philadelphia chromosome positive B-cell acute lymphoblastic leukemia; SD: sudden death; TdP: torsades de pointes; TKI: tyrosine kinase inhibitor. ABL: Abelson tyrosine kinase; CSF1R: colony-stimulating factor 1 receptor; EGFR: epidermal growth factor receptor; HER2: human epidermal growth factor receptor 2; hERG: human ether a-go-go related gene; FLT3: FMS-related tyrosine kinase; mTOR: inhibitor of mammalian target of rapamycin; NOS: nitric oxide synthase; NRTK: nonreceptor tyrosine kinase; PDGFR: plateled-derived growth factor receptor; PGI2: prostaglandin I2; RAF: serine/threonine-protein kinase-transforming protein; RET: rearranged during transfection; VEGFR: vascular endothelial growth factor receptor. a Therapeutic target(s) are highlighted in bold. b Data from www.thomsonhc.com, DRUGDEX® Drug Summary Information. Last access 30/04/2009. c Effect on ventricular function has not been scrutinized.

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Table 3 Trastuzumab cardiotoxicity: summary from adjuvant studiesa. Trial

Follow-up Treatment (months) arm(s)

Baseline LVEF evaluation (months) LVEF (%)

HERA (n = 3386) (Suter et al., 2007) NCCTG N9831 (n = 1334) (Perez et al., 2008b)

23.5

≥ 55d

18

NSABP B-31 (n = 1845) 28.8 (Tan-Chiu et al., 2005; Rostogi et al., 2007) BCIRG006 (n = 3174) 36 (Slamon et al., 2006) FinHer (n = 232) (Joensuu et al., 2006) ECOG E2198 (n = 234) (Sledge et al., 2006)

37

PASC 04 (n = 528) (Spielmann et al., 2007)

48

64

CT alone CT→T AC→P AC→P→T AC→PT AC→P AC→PT AC→D AC→DT DCT D or V→FEC TD or TV→FEC PT→AC PT→AC→T FEC→T DE→T

≥ 50f

≥ 50f ≥50k

NR ≥ 50k ≥ 55m,d

Severe LVEF Discontinuation Cardiac CHF(%)b drop (%) (%)c deaths (n)

Baseline, 3, 6, 12, 18, 24, 30, 36, 60 0 by MUGA or ECHO 0.6 Baseline, after AC, 6, 9, 18, 21 0.3g by MUGA or ECHO 2.8g 3.3g Baseline, after AC, 6, 9, 18 by MUGA 0.8i 4.1i Baseline, 3, 6, 9, 18 by MUGA 0.4 and ECHO 1.9 0.4 Baseline, after FEC, 12, 36 after NR chemo by MUGA or ECHO 0 NR 2.6 3.6 NR 1.7 0.4

0.53e 3.04e 6.7h 17.3h 15.9j NR 10.1l 18.1l 8.6l 6.0h 3.5h NR

NA 4.3 15.4 NA NA 18.9 NR NA 8.3 3.6 NA NR NR

4.2n 2.2n

17.9 NA

1 0 1 1 0 1 0 0 0 0 0 0 0 0 0 0

NA: not available; NR: not reported. AC: doxorubicin and cyclophosphamide; CT: chemotherapy; D: docetaxel; DCT: docetaxel, carboplatin and trastuzumab; E: epirubicin; ECHO: echocardiography; FEC: fluorouracil, epirubicin and cyclophosphamide; LVEF: left ventricular ejection fraction; MUGA: radionuclide ventriculography multiple-gated acquisition scan; P: paclitaxel; T: trastuzumab; V: vinorelbine. BCIRG 006: Breast Cancer International Research Group trial; ECOG E2198: Eastern Cooperative Oncology Group trial; FinHer: Finland Herceptin trial; HERA: Herceptin Adjuvant trial; NCCTG N9831: North Central Cancer Treatment Group trial; NSABP B-31: National Surgical Adjuvant Breast and Bowel Project trial; PACS 04: Protocole Adjuvant dans le Cancer du Sein trial. a Results from BCIRG006, ECOG E2198 and PASC 04 have not been published. b NYHA grade III or IV not including cardiac death. c Because of cardiac-related problems. d Post-chemotherapy and pre-trastuzumab. e Decline N 10% and below 50% with confirmation after ∼3 weeks. The incidence of at least one significant LVEF drop at any time was also significantly higher in the trastuzumab group (7.03% vs. 2.05%). f Post-chemotherapy. g 3-year cumulative incidence. h Decrease in LVEF ≥ 15% from baseline at any time point. i 5-year cumulative incidence. j Decline N10% and below 55% with no confirmation. k Pre-chemotherapy. l Symptomatic CHF including severe. m Or between 50 and 55 with cardiologist approval. n Asymptomatic LVEF decline.

effects of a novel trastuzumab regimen (i.e. PTX and short-term trastuzumab) prior to DOXO plus cyclophosphamide (FEC) and then followed by a 1-year therapy with trastuzumab. Although possibly underpowered, this study had CHF as an endpoint, which was reported in four patients receiving adjuvant trastuzumab. The PACS 04 study (Spielmann et al., 2007), a multicenter, open-label, randomized controlled trial, has the longest follow-up reported to date and reflects exclusively cardiotoxicity associated with trastuzumab (patients were randomized after completion of chemotherapy and those with compromised cardiac function were excluded). Interestingly, the overall risk of CHF reported in NSABP B-31 (4%) is significantly higher than in HERA (0.6%). Likewise, the overall rates of severe CHF, LVEF drop and discontinuation because of cardiacrelated problems are very different between the two studies. These intriguing findings might be explained taking into account that: – The entry criterion was LVEF N 50% before starting trastuzumab in NSABP B-31, whereas it was N55% in HERA. – Patients who experienced a drop in LVEF following anthracyclinebased chemotherapy would not have been eligible for HERA; therefore, those patients at higher risk to develop heart failure were excluded. – Patients enrolled in HERA included even those without prior anthracycline treatment. – The time between completion of chemotherapy and the start of trastuzumab in NSABP B-31 was shorter (21 days vs. 89). Sequential therapy, indeed, has gained consensus as safer than concurrent regimen.

– Trastuzumab was associated with paclixatel (known to affect cardiac function) in NSABP B-31. – The use of epirubucin, a DOXO isomer thought to be less cardiotoxic than the parent drug, was extensive in HERA. – The definition of contractile dysfunction was different between trials. In HERA, a significant LVEF drop was defined as an absolute decline of at least 10 percentage points from baseline LVEF and to below 50% (with requested confirmation after 3 months). In NSABP B-31, a significant (asymptomatic) LVEF drop was defined as a single drop of ≥10 percentage points and to below 55% (without confirmation needed). The rate of confirmed LVEF drop in HERA (3%) may be indeed underestimated: an incidence of 7% was found when considering the occurrence of only one significant LVEF drop without confirmation. In contrast to anthracycline cardiotoxicity, which is irreversible, dose-dependent and associated with ultrastructural changes, trastuzumab-associated cardiac dysfunction is thought to be idiosyncratic and at least partially reversible since no structural damage has been detected by myocardial biopsies of patients. This form of “hibernation” with loss of contractility posed the basis to distinguish type I and type II chemotherapy-related cardiac dysfunction (Ewer & Lippman, 2005). Another aspect of trastuzumab-related cardiotoxicity is the fact that the recovery after discontinuation was almost complete and, especially, re-challenge was generally well tolerated. A retrospective review of 38 patients experiencing cardiac dysfunction after trastuzumab found that all recovered and 22 of 25 who underwent rechallenge showed no recurrent decrease in LVEF (Ewer et al., 2005).

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Guarneri et al. (2006) found that of 26 patients who recovered from a LVEF drop and were restarted on the drug, 16 (61%) showed no further cardiac toxicity. Of the 10 patients who developed recurrent cardiac toxicity, 5 had full recovery with drug discontinuation. In a recent study (Wadhwa et al., 2009), only 11% of the patients who developed cardiotoxicity were rechallenged with concomitant use of ACE inhibitors and beta blockers with no reoccurrence of ventricular dysfunction. Reversibility of cardiac damage has been further substantiated by follow-up data from the HERA and NSABP B-31 trials. However, because a significant proportion of patients (nearly 1/ 4) experienced a persistent LVEF drop, Telli et al. (2007) recently stressed the notion that complete recovery could not be demonstrated especially in the NSABP B-31 trial. Although actually a 100% recovery was not documented, we should not overlook the fact that all patients had also received an anthracycline. Therefore, the relative contribution of anthracyclines to trastuzumab-associated cardiotoxicity cannot be estimated conclusively. At the present state of knowledge, it seems that we are dealing more with an anthracycline-related problem than with residual trastuzumab-related toxicity (Ewer & Tan-Chiu, 2007). Nevertheless, late-onset cardiac toxicity remains a potential issue and the need for long-term follow-up is undisputed. 3.1.2. Molecular mechanisms and proposed targets In adult human heart, trastuzumab alone causes a contractile dysfunction that develops independently of the dose and generally does not show ultrastructural changes (e.g. myofibrillar disarray), which, instead, are typical of the irreversible damage caused by anthracyclines. Although the precise mechanism is still unclear, disruption of the HER2 signalling cascade within the heart is thought to play a major role. Several lines of evidence support the critical involvement of HER2 in cardiomyocyte development and survival (Lee et al., 1995; Meyer & Birchmeier, 1995; Zhao et al., 1998; Kuramochi et al., 2006). Neuregulin 1 (NRG1) is produced by cardiac endothelial cells, binds the human epidermal growth factor receptor 4 (HER4, also known as ERBB4) on cardiomyocytes and promotes heterodimerization with HER2, leading to activation of various downstream intracellular signalling pathways: ERK-MAPK (mitogen-activated protein kinase), phosphatidylinositol 3-kinase P13KAkt pathways and Src-FAK (focal adhesion kinase). Mouse models suggested that ERBB2, ERBB4 and Nrg1 knockout are embryonically lethal (Lee et al., 1995; Gassmann et al., 1995; Meyer & Birchmeier, 1995). Moreover, a critical role for HER2 in cardiac integrity was demonstrated in a mouse model with a cardiac-restricted conditional HER2 deletion mutant. These mice were viable, developed a dilated cardiomyopathy, had decreased survival after pressure overload stress and were more sensitive to anthracycline-mediated cardiomyopathy (Ozcelik et al., 2002; Crone et al., 2002). Conversely, HER2 upregulation was found in the heart within 3 weeks of antracycline therapy, but not in heart failure unrelated to antracycline treatment (de Korte et al., 2007). Taken together, these findings may provide a clue to explain the higher incidence of cardiotoxicity in patients treated with a concurrent antracycline and trastuzumab regimen as compared to a sequential schedule. Recent investigations revealed that NRG-1 carried an important role even in the adult heart, where it is involved in the regulation of cardiac sympatho-vagal balances by counterbalancing adrenergic stimulation through an obligatory interaction with the muscarinic cholinergic system (Lemmens et al., 2007). Therefore, NRG-1 is emerging as promising target that might pave the way for future research (Xu et al., 2009; Pentassuglia & Sawyer, 2009). In summary, the higher than expected incidence of cardiotoxicity in patients treated with concomitant anthracyclines and trastuzumab regimens may be indeed the result of synergistic mechanisms: (a) interference with cardioprotective mechanisms of the heart and (b) enhanced susceptibility to cardiotoxicity induced by anthracyclines. In other words, trastuzumab may not only provide an additional insult

(probably largely reversible) to the cardiac damage caused by the anthracycline component, but also hinder cell repair within the vulnerable heart, thus potentiating cardiac dysfunction. Although ERBB2 inhibition is implicated as a key mechanism of trastuzumab-related cardiotoxicity, the pathophysiology is probably more complex. Recent observations revealed minimal cardiotoxicity for lapatinib, an orally available dual kinase inhibitor of epidermal growth factor receptor (EGFR) and ERBB2 (Geyer et al., 2006; Bilancia et al., 2007; Perez et al., 2008a). Cardiac events were usually asymptomatic and largely reversibile, suggesting a cellular dysfunction rather than myocyte damage. The underlying mechanisms have not been sufficiently elucidated, but seem to involve the activation of the cytoprotective AMP-activated protein kinase (AMPK) in cardiomyocytes (Spector et al., 2007). An alternative explanation calls into question the antibodydependent cell-mediated cytotoxicity (ADCC) effect of trastuzumab. This immune-mediated effect has been demonstrated in HER2positive tumor cells in vitro (Sliwkowski et al., 1999). However, the low cardiotoxic potential of pertuzumab (another HER2 inhibitor) in early clinical trials does not support ADCC to play a primary role in the pathogenesis of cardiotoxicity (Gordon et al., 2006). A further speculative mechanism concerns a unique intracellular signalling response of cardiomyocytes to HER2. In rat cardiomyocytes, trastuzumab administration results in downregulation of the antiapoptotic protein BCL-XL and upregulation of the pro-apoptotic protein BCL-XS leading to loss of mitochondrial membrane potential, reduction in the level of ATP, cytochrome c release and caspase activation (Grazette et al., 2004). 3.1.3. Current options to reduce trastuzumab cardiotoxicity 3.1.3.1. Trastuzumab-toxin conjugates. Antibodies can be used to deliver cytotoxic agents specifically to antigen-expressing tumors. This chemical linkage can be viewed not only to confer higher tumor selectivity but also to conferring cell killing power to monoclonal antibodies that are tumor-specific, but not sufficiently cytotoxic (Chari, 2008). As a matter of fact, a reduced toxicity is expected, as recently demonstrated for trastuzumab, which has been linked to the fungal toxin maytansine DM1 (Lewis Phillips et al., 2008). 3.1.3.2. Short-course regimen of trastuzumab before anthracyclines. This type of approach has great appeal because of clinical implications in terms of safety and cost–benefit profile. Although not specifically designed to address this issue, the FinHer trial and the pilot study Eastern Cooperative Oncology Group (ECOG) E2198 corroborated this approach. In the FinHer trial (Joensuu et al., 2006), a subset of 232 HER2positive patients was randomized to receive chemotherapy (either DTX or vinorelbine) followed by fluorouracil, EPI and FEC in all groups and a further randomization to 9 weeks trastuzumab or to DTX or vinorelbine in those with HER2 amplification. No cases of heart failure were detected in the 9 week-trastuzumab arm and a negligible LVEF effect was detected. However, given the small size of the trial, the results should be interpreted with caution. A further promising trial (ECOG E2198) showed similar rate of cardiotoxicity to other 1-year trastuzumab trials (i.e. B-31 and N9831) with no reported cardiac deaths (Sledge et al., 2006). 3.1.3.3. Non-anthracycline-based regimens. The substantial cardiotoxicity of anthracycline and trastuzumab co-administration has generated interest in non-anthracycline trastuzumab-based regimens, particularly now that evidence has emerged on efficacy of non-anthracycline regimens in the adjuvant setting. The BCIRG 006 trial (Slamon et al., 2006) provided direct head-to-head comparison of carboplatin, DTX, and trastuzumab with the standard regimen of DOXO, FEC, and DTX. This trial showed for the first time that a non-anthracycline-containing regimen with trastuzumab has equivalent efficacy in decreasing the

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recurrence of breast cancer, with less incidence of cardiotoxicity when compared to anthracycline-containing trastuzumab adjuvant regimens. Moreover, the Xeloda in Neoadjuvant (XeNA) trial (Gluck et al., 2008) identified Capecitabine plus DTX and trastuzumab with DTX as promising non-anthracycline regimens for the preoperative treatment of women with HER2-negative and HER2-positive breast cancer, respectively. 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 (Gianni et al., 2009). 3.1.3.4. Towards individualized anthracycline use. The fact that topoisomerase II alpha (TOP2A) protein is the molecular target of anthracyclines raised interest on the possibility to tailor their use on the basis of expression of this protein. Aberrations of the TOP2A gene, located next to the HER2 gene, are more frequent in HER2-amplified than HER2-nonamplified tumors. The original report (Muss et al., 1994) and a number of other reports and retrospective investigations, including a recent pooled analysis, found an additional benefit of anthracycline-containing regimens in HER2-positive breast cancer, challenging the use of adjuvant anthracyclines in patients with HER2negative tumors (Di Leo et al., 2002; Di Leo & Isola, 2003; Olsen et al., 2004; Knoop et al., 2005; Villman et al., 2006; Tanner et al., 2006; Park et al., 2006; Arriola et al., 2007; Gennari & Pronzato, 2008; Pritchard et al., 2008; Di Leo et al., 2008). On the other hand, others reported opposite findings (Bartlett et al., 2008). In the wake of the results from the BCIRG 006 trial, investigators proposed that anthracycline-containing chemotherapy may not be required in HER2-overexpressing women, and/or that trastuzumab may not be necessary in addition to an anthracyclinecontaining regimen in women with HER2/TOP2A coamplified tumors (Mackey et al., 2009). Overall, these findings do not allow to draw definite conclusions and the option to treat with an adjuvant anthracycline regimen patients with co-amplification of HER2 and TOP2A genes remains controversial (Slamon & Press, 2009; Pritchard, 2009). 3.1.3.5. Focussing on alternative targets. Lapatinib, a kinase inhibitor targeting internal HER2 and EGFR, increased survival in patients with advanced HER2-overexpressing breast cancer when given in combination with the chemotherapeutic agent capecitabine (Geyer et al., 2006). In the wake of the experience with trastuzumab, prospective evaluation of cardiac function was mandatory during early phases of lapatinib development and failed to detect significant cardiotoxicity (Perez et al., 2008a). A review of 44 clinical studies enrolling 3689 patients receiving lapatinib revealed a 0.2% rate of symptomatic CHF and a 1.4% rate of asymptomatic cardiac events. However, it should be noted that patients were heterogeneous and the interval between anthracycline and lapatinib administration was longer than in any trastuzumab trials. Although further studies should be performed to corroborate these findings, the activation of the cytoprotective AMPactivated protein kinase (AMPK) in cardiomyocytes may at least partially explain the safer cardiac profile of lapatinib as compared to trastuzumab (Spector et al., 2007). Thus, the favorable cardiac profile together with the convenience of oral use and, theoretically, with the benefit in preventing brain metastasis (Lin et al., 2008; Gluck & Castrellon, 2009; Lin et al., 2009) supports lapatinib to have a potential role as first-line therapy in the adjuvant and neoadjuvant settings (Gomez et al., 2008). The TEACH (Tykerb Evaluation After Chemotherapy), ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) and CHERLOB (Preoperative Chemotherapy plus Lapatinib or Trastuzumab or Both in HER2-positive Operable Breast Cancer) trials, currently ongoing, will clarify this issue.

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Bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF) receptor, has shown benefits in the treatment of many types of malignancy; it has been recently approved by the US FDA in metastatic breast cancer. In a recent study, the combination of bevacizumab with PTX showed an improved progression-free survival for patients with previously untreated metastatic breast cancer (Miller et al., 2007). On the other hand, physicians should be aware of the recognized risk of arterial thromboembolic events (Scappaticci et al., 2007) and venous thromboembolism, as recently revealed by a meta-analysis (Nalluri et al., 2008). Thus, stringent cardiac surveillance is advisable. The BETH study (the Bevacizumab and Trastuzumab Adjuvant Therapy in HER-2-Positive Breast Cancer) will provide insight into the safety and efficacy of combining targeted therapy. 3.2. Tyrosine kinase inhibitors Small-molecule TKIs have changed the view labelling cancer as a lethal disease, all the more so because of recent improvements in terms of disease-free survival and quality of life (lower rate of typical side effects such as nausea, vomiting and hair loss as compared to conventional chemotherapy). Despite this success, recent investigations revealed unexpected cardiac side effects, including ventricular dysfunction and CHF (Kerkela et al., 2006; Chu et al., 2007). 3.2.1. Imatinib and other Abelson tyrosine kinase inhibitors Imatinib represents an excellent example of how the discovery of the proper target may drive drug design and development: it is an ATP-competitive TKI of the Abelson tyrosine kinase (ABL) that has been developed mainly to treat leukemic cells expressing the breakpoint cluster region (BCR)-ABL fusion protein encoded by the Philadelphia chromosome (Ph). It also inhibits growth factor receptor of the tyrosine kinase subclass III family c-Kit (also known as CD117) and plateled-derived growth factor receptor (PDGFR), which are targets in gastrointestinal stromal tumors (GISTs). The imatinibresistant mutant ABL T315I was found to rescue cells from imatinibinduced toxicity hence supporting ABL as an important antitarget for cardiac damage (Gorre et al., 2001). These findings led Fernandez's group to engineer a variant of imatinib, WBZ_4, retaining only activity against c-Kit. WBZ_4 was found to be as effective as imatinib in mouse models of GIST but did not cause cardiomyocyte dysfunction (Fernandez et al., 2007b). The extent of imatinib-induced cardiotoxicity is still under scrutiny. The original observation by Kerkela et al. (2006) reported modest, but consistent, decline in LVEF, but more striking was a loss of myocardial mass, consistent with cell loss. In response to this work, several letters were published, all of them suggesting a low incidence of CHF: 0.5% to 1.7% (Rosti et al., 2007; Hatfield et al., 2007; Gambacorti-Passerini et al., 2007; Atallah et al., 2007b). Likewise, large clinical trials (O'Brien et al., 2003; Druker et al., 2006; Kantarjian et al., 2006b) and several reports (Verweij et al., 2007; Atallah et al., 2007a; Perik et al., 2008) questioned the clinical relevance of adverse cardiac effects, suggesting that CHF could be very uncommon in the overall population exposed to imatinib, but can indeed occur in elderly patients with pre-existing cardiac conditions. A recent prospective cross-sectional study failed to detect long-term systematic cardiotoxicity in “real world” patients although isolated cases cannot be ruled out (Ribeiro et al., 2008). Mitochondrial dysfunction represents the molecular basis subtending imatinib-induced cardiac injury. Unlike with trastuzumab, the induction of endoplasmic reticulum (ER) stress by unfolded proteins may play a critical role. ER stress activates two distinct pathways mediated by ER-resident eukaryotic translation initiation factor 2α kinase (PERK) and by inositol-requiring enzyme 1 (IRE1) (Ron, 2002; Zhang & Kaufman, 2006a; Zhang & Kaufman, 2006b). Cardiomyocytes treated with imatinib had increased phosphorylation

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of the eukaryotic translation initiation factor 2α (EIF2α), the substrate of PERK. Moreover, the IRE1 pathway recruits Jun N-terminal kinases (JNKs) (Ron, 2002). Of note, both salubrinal, a compound that prevents dephosphorylation of EIF2α, and WBZ_4, an inhibitor of JNKs (Fernandez et al., 2007b; Fernandez & Sessel, 2009), prevented imatinib-induced cell death. In addition, the pro-apoptotic action of protein kinase Cδ (PKCδ) in the heart may be involved in imatinib cardiotoxicity (Steinberg, 2004). Since the therapeutic benefit of imatinib is undisputed, the question arises whether/when cardiotoxicity should limit its therapeutic use, all the more so because in many cases the relevance of subclinical cardiotoxicity is at present unknown. Of course, the approach proposed by Fernandez et al. (2007b) and discussed above holds great promise to create effective and safe therapeutic agents. As regards other ABL inhibitors, both dasatinib and nilotinib, which are used in some imatinib-resistant mutants, have been implicated in the development of CHF as well as edema, QT interval prolongation and sudden cardiac death. However, a number of kinases may have a direct or indirect role in the pathophysiology of cardiotoxicity: dasatinib has been demonstrated to be a potent inhibitor of all Src family kinases (Kantarjian et al., 2006a). 3.2.2. Multitargeted tyrosine kinase inhibitors The use of multitargeted TKIs such as sorafenib and sunitinib is likely to increase in the next years because of promising benefits in various cancers, their oral administration and manageable adverse events. However, the incidence of cardiac side effects seems to be higher than previously reported and a recent report found unexpected cardiotoxicity after sequential use of these agents (Mego et al., 2007). Schmidinger et al. (2008) estimated an incidence of LVEF drop of 5% for sorafenib and 14% for sunitinib. Sorafenib, approved for metastatic renal cell carcinoma (MRCC) and hepatocellular carcinoma (HCC), targets serine/threonine-protein kinase-transforming protein RAF-1, vascular endothelial growth factor receptor 2/3 (VEGFR2/3), FMS-related tyrosine kinase 3 (FLT3), c-Kit and PDGFRs. The functional implication of RAF-1 in cardiac performance has been demonstrated in mouse models emphasizing a protective role in the heart, particularly in the setting of pressure overload stress (Harris et al., 2004). Its deletion led to a dilated, hypocontractile heart with enhanced cardiomyocyte apoptosis and fibrosis (Yamaguchi et al., 2003). RAF-1 inhibits two pro-apoptotic kinases having a role in oxidant stress-induced injury: apoptosis signal-regulating kinase (ASK1) and mammalian sterile 20 kinase 2 (MST2) (Muslin, 2005). An open question is whether sorafenib also disrupts molecular interactions with these kinases. Will et al. (2008) using an in vitro approach, examined the effect of multitargeted TKIs on mitochondrial function and suggested direct mitochondrial impairment to have a role in sorafenib cardiotoxicity. At the present state of knowledge, however, hypertension seems to be the major cardiovascular adverse reaction associated with sorafenib (Escudier et al., 2009). In addition, a recent report documented the cardiac safety of sorafenib in a patient with sunitinib-induced CHF (Wong & Jarkowski, 2009), but vigilance on this aspect is still advisable. Concerning sunitinib, results from two trials and a retrospective analysis of phase I/II trials showed that up to 11% of treated patients experienced a significant decline in LVEF (Demetri et al., 2006; Chu et al., 2007; Motzer et al., 2007), despite no reported clinical sequelae after discontinuation. Recent retrospective analysis at Stanford University found relevant cardiotoxicity: 15% of a cohort of 48 patients developed symptomatic grade III/IV CHF (Telli et al., 2008). Moreover, another investigation described that 2.7% of patients who received sunitinib developed CHF that resulted in substantial morbidity and, in some cases, mortality (Khakoo et al., 2008). The only partial recovery suggests that cardiotoxicity may represent a potentially serious concern for sunitinib and underscores the need for careful monitoring (Theou-Anton et al., 2009). Strategies for dose modifications and clinical management have

been published (Hutson et al., 2008). Although a number of studies have been conducted to identify mechanisms subtending heart damage, the exact antitarget(s) is unclear. Scanning the kinase receptor map supposed several candidates, including the ribosomal S5 kinase (RSK1) and AMP-activated protein kinase (AMPK) (Terai et al., 2005; Dyck & Lopaschuk, 2006), although further investigations argued that inhibition of other kinases is likely to cause sunitinib-associated cardiotoxicity (Hasinoff et al., 2008). Additional concern regards the high incidence of hypertension associated with VEGFR inhibitors deserving special attention in patients with poorly controlled hypertension (Shiojima et al., 2005; Izumiya et al., 2006). Hypertension and reported hypothyroidism (Desai et al., 2006) may contribute to the occurrence or exacerbation of CHF: this aspect is still unclear and deserves further evaluation. Blood pressure should be frequently monitored, all the more so because hypertension has been recently identified as an independent predictor of CHF (Di Lorenzo et al., 2009). In any case, cardiac complications associated with multitargeted TKIs are inherently related to their non-selectivity but may be circumvented, at least theoretically, by drug redesign to avoid inhibition of key factors implicated in cardiac survival. As recently illustrated by Fernandez & Sessel (2009), SUDE (sunitinib-derived editor) represented the re-engineered product of sunitinib (also known as “scaffold”) that may act as sorafenib editor. SUDE overlaps with sorafenib on the therapeutic targets VEGFR, c-Kit, PDGFR and FLT3, but counteracts detrimental signalling cascade in cardiomyocytes through its anti-MST2 activity. Likewise, the re-engineered version of imatinib WBZ_4 behaves as an editor and interferes with the downstream pathway involved in sorafenib-related cardiotoxicity. 3.2.3. Other potential antitargets responsible for cardiotoxicity Because of the role of kinases in the fine tuning between survival and apoptosis, a number of potential antitargets resulting in cardiotoxicity are expected (Force & Kerkela, 2008). Several lines of evidence drew the attention to EGFR, c-Kit and janus kinase (JAK)-STAT (signal transducer and activator of transcription) inhibition. Erlotinib, an EGFR inhibitor approved for lung and pancreatic cancer, has been implicated in myocardial injury induced by isoproterenol infusion, suggesting EGFR signalling to be protective in settings of catecholamine excess (Noma et al., 2007). Animal studies raised potential concern on possible cardiovascular side effects related to c-Kit inhibition, especially in patients with a history of coronary artery disease. The blockade of this pathway may aggravate pathological heart modelling after myocardial infarction and prevent repair (Ayach et al., 2006; Cimini et al., 2007; Fazel et al., 2008). Concerning the JAK/STAT pathway, available data suggest that its activation is essential for the cardioprotection by ischemic preconditioning (Boengler et al., 2008). Lestaurtinib, the most advanced JAK inhibitor in clinical development for acute monocytic leukemia, has not shown significant cardiotoxicity in phase I/II trials, although prospective cardiac evaluation has not yet been performed. 4. Early detection and monitoring 4.1. Issues during drug development It is generally accepted for all compounds before marketing authorization that pre-clinical findings should guide the safety cardiac monitoring during subsequent human studies. However, because of pitfalls of non-clinical models to detect cardiotoxicity (Robert, 2007), the early prediction of clinical behavior of drugs represents an open challenge in pre-clinical phase. For instance, in the case of QT prolonging drugs, the regulatory ICH S7B guideline describes a non-clinical testing strategy to identify the potential of a test substance to delay ventricular repolarisation. The sensitivity of in vitro/in vivo tests (i.e. their ability to label as positive those drugs with a real risk of inducing QT prolongation in humans) is sufficiently good, but their specificity (i.e. their ability to label as negative those drugs carrying no risk) is not well established.

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Because the “gold standard” assay currently does not exist, an integrated risk–benefit assessment encompassing several models supports accurate decision-making and is recommended by regulatory guidelines (Recanatini et al., 2005; Raschi et al., 2008). The scant comprehension of the molecular basis subtending cardiotoxicity further complicates reliable prediction and early detection during the pre-marketing phase, all the more so because recognized surrogate endpoints are currently lacking. In the wake of experience with trastuzumab, which did not undergo pre-clinical safety assessment but caused significant cardiac dysfunction in clinical trials when co-administered with anthracyclines, effective screening is needed in the early phase of drug development. Primary cardiomyocytes currently represent established models in toxicological test systems. Embryonic stem cell-derived and differentiated cardiomyocytes are promising models which may expand resources and improve predictivity of non-clinical tests (Kettenhofen & Bohlen, 2008). Indeed, the predictivity of the currently used animal models is undetermined. Although many alternative approaches are being developed [e.g. the zebrafish model (Barros et al., 2008; Berghmans et al., 2008)], it should be kept in mind that basic safety studies may help to clarify the molecular basis of drug-induced cardiac dysfunction, but do not predict clinical outcomes. In any case, biotechnology and bioengineering approaches are essential to increase specificity in rational drug design and may be used not only to overcome drug resistance (Fernandez et al., 2007a; Crespo et al., 2008), but also to enhance the safety profile of a promiscuous agent (Fernandez et al., 2007b; Zhang et al., 2008). For instance, packing defects of soluble proteins have been exploited as promising molecular targets to achieve specificity (Fernandez & Scheraga, 2003; Crespo & Fernandez, 2007; Fernandez et al., 2009a). 4.2. Issues in clinical practice The clinical monitoring and follow-up of both newly diagnosed patients and long-term cancer survivors is an intriguing problem. Apart from an existing guideline on children's monitoring during anthracycline therapy (Steinherz et al., 1992), most current recommendations rely on physicians' personal experience, as indicated by a recent review showing substantial heterogeneity among protocols of European pediatric oncology trials (van Dalen et al., 2006a). In patients treated with an anthracycline regimen, the need for monitoring, even after the completion of therapy, depends on the clinical aspects that physicians might face in daily practice: dosedependent (cumulative), delayed (late-onset), progressive and irreversible cardiotoxicity (Ewer & Lippman, 2005). Moreover, depending on personal risk background, the threshold cumulative dose may be lower than previously assumed (Ryberg et al., 2008). Although the assumption that all patients undertaking anthracyclines therapy require baseline cardiac evaluation has been questioned (Porea et al., 2001; Sabel et al., 2001), it is widely accepted to assess cardiac function before treatment in order to plan further regular evaluation (Jannazzo et al., 2008). Steinherz et al. pioneered attempts to develop recommendations on appropriate follow-up monitoring (Steinherz et al., 1992). The frequency of monitoring depends on the age at therapy, radiation dose and cumulative anthracycline dose (i.e. on the patient risk profile). Important suggestions could be found in a recent report from the Task Force of the Children's Oncology (Shankar et al., 2008). Although several host- and drug-related risk factors have been recognized for anthracyclines (Lipshultz et al., 2008), the identification of sub-populations at risk for developing cardiotoxicity requires insight and understanding of the genetic and epigenetic contribution: their incorporation into the next monitoring schemes is strongly advised. Concerning targeted drugs, little is known on the long-term cardiac effects and, with few exceptions (e.g. trastuzumab), on the reversibility of the phenomenon. The main limitation of the existing data concerns the median follow-up (between 2 and 3 years for trastuzumab) that carries a

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further clinical implication: there is no information whether recovery from CHF by medical therapy is permanent or will potentially increase the risk of late cardiac dysfunction. Moreover, a systematic identification and analysis of risk factors associated with cardiotoxicity has not been performed. In this light, a careful evaluation of cardiac function should be recommended in all eligible patients, especially in case of reduced myocardial reserve (i.e. concomitant co-morbidities). Moreover, the fact that recognizing drug-induced CHF in cancer patients is complicated by symptoms of other underlying conditions leading to dyspnoea, fatigue and edema together with the large number of compounds under development calls for an active surveillance also during the postmarketing phase. A further limiting step pertains to the inherent limitation of LVEF in quantifying CHF. Common cut-off values used for defining presence or absence of cardiac impairment are arbitrary and introduce selection bias (De Keulenaer & Brutsaert, 2007). Moreover, a markedly depressed regional systolic function may be found in patients with normal ventricular function (Sanderson & Fraser, 2006). Thus, the actual prevalence of cardiotoxicity may be clearly underestimated (Schmidinger et al., 2008). The clinical relevance of this sub-clinical damage is actually undefined. In this context, the benefit–risk balance between the therapeutic gain (in terms of life expectancy) and the risk of cardiotoxicity should be evaluated depending on the clinical scenario: the risk of late-onset cardiotoxicity is not so relevant in the setting of terminal cancer, whereas early detection of cardiotoxicity remains a significant concern in long-term survivors. To sum up, there is an urgent need to monitor patients with cancer in order to early detect and correctly manage potential cardiotoxicity in clinical practice (Altena et al., 2009). Table 4 summarizes strategies to actively monitor patients at risk. Several methods are available, including invasive and non-invasive techniques. Advantages and limitations should be taken into account and support the use of several methods for an accurate management (Jurcut et al., 2008). In any case, the baseline risk should be first evaluated in order to identify vulnerable patients because of individual susceptibility (e.g. genetic background). Combining an imaging technique [e.g. ECHO with Doppler or ventriculography multiple-gated acquisition (MUGA) scan] with specific cardiac biomarkers [e.g. cardiac troponin (cTnT) or brain natriuretic peptide (BNP)] is promising (Germanakis et al., 2006; Horacek et al., 2007; Urbanova et al., 2008; Dodos et al., 2008; Mavinkurve-Groothuis et al., 2008; Dolci et al., 2008; Mavinkurve-Groothuis et al., 2009). At present, a series of considerations on costs and feasibility in the “real-world” suggest that ECHO plays an important role for monitoring cardiac toxicity of anticancer agents. This non invasive technique allows to assess changes in systolic and diastolic function, as well as to rule out pericardial effusion and pulmonary hypertension. Diastolic parameters have been recently labelled as attractive and sensitive surrogates of early changes in cardiac performance: mitral inflow pattern early/atrial (E/A) ratio, strain rate and the Tei-index has been introduced to study the impact of anthracyclines on ventricular function with promising preliminary results (Dodos et al., 2008). Assessment of LVEF and of its early changes is a crucial step in monitoring cardiac toxicity; however, clinical use of this technique should require special attention in order to minimize intra-observer and inter-observer variability during serial measurements of LVEF. It should also be recognized that LVEF changes are a late finding, which may come to the forefront only when cardiac reserves are insufficient to counteract the pump failure. Moreover, serum biomarkers are a promising strategy for early detection of cardiotoxicity (O'Brien, 2008), although the actual effectiveness of these markers has been recently questioned by Bryant et al. (2007) who found that “evidence on the use of cardiac markers for quantifying cardiac damage is limited in quantity and quality making conclusions problematic”. The authors acknowledged that “the use of effective cardiac markers would impact not just on clinical effectiveness but also the cost effectiveness of anthracycline therapy which is an additional important consideration”.

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Table 4 Methods to monitor anticancer-induced cardiotoxicity: advantages and drawbacks. Technique No longer used EB

Current standard ECHO

MUGA

ECG

Promising DMI

Stress ECHO

MRI

CT

Scintigraphy Biomarkers

Endothelial damage Genetic tests

Strengths

Limitations

Traditionally (albeit wrongly) viewed as the “gold standard” Histological evidence of cardiac damage

Invasive nature It requires specialist training to perform and interpret results Small sample of myocardial tested No functional data of myocardial performance and clinical status of patients

Harmless and cost-effective Morphological and functional evaluation: systolic (LVEF, LV shortening fraction, systolic wall thickening) and diastolic (E/A ratio, isovolumetric relaxation time, pulmonary venous flow pattern) parameters Information on structural valve and pericardium changes Established and well-validated to determine ejection fraction High reproducibility Low inter-observer and intra-observer variability

Operator-dependent (intra-observer and inter-observer variability) LVEF assessment is image-quality dependent and subject to variability Unclear predictive value for early detection of subclinical damage

It underestimates ventricular volumes It overestimates ejection fraction for smaller ventricles (children and women) Invasive nature (radiation) Low temporal and spatial resolution No information on valve function Scant information on diastolic function Limited predictive value for early detection of subclinical damage No information on LVEF Intra- and inter-subject variability in QT values Problems in measurement, analysis and interpretation of QT interval

Harmless and cost-effective to screen for arrhythmia QT interval prolongation is recognized as surrogate marker of cardiotoxicity

Limited experience Additional time to analyse data

Powered to detect isolated diastolic dysfunction Early detection of subclinical damage (combined with inflammatory/oxidative stress markers): Tei-index Excellent temporal resolution Functional evaluation: diastolic (E/A ratio) and systolic measurement of velocities of ventricular walls, deformation (strain) and deformation rate (strain rate) Evaluation of contractile myocardium reserve (detection of cardiac dysfunctions remaining occult at rest) Highly reproducible Functional and perfusion myocardial evaluation: identification of post-infarction scar and viable myocardium (combined with late gadolinium contrast enhancement) Tissue characterization Useful in patients with limited echocardiography windows High image quality (similar to MRI)

Non invasive nature Structural and functional evaluation Minimally invasive Low inter-observer variability cTnT, BNP and glycogen phosphorylase BB are promising markers to early detect myocardial injury (highly sensitive and specific) Baseline cardiac assessment and potential signals of cardiac damage Cytokines, adhesion molecules and carotid intima-media thickness are potential surrogate endpoints of cardiotoxicity Minimally invasive Identification of susceptible patients (baseline risk evaluation)

Limited and controversial data on early detection of cardiotoxicity in patients with cancer Semi-invasive nature Low temporal resolution High costs of repeated examinations Limited availability Preliminary evidence on predictive value

High radiation dose Limited availability Low temporal resolution Limited data Not routinely used in standard clinical practice Undefined predictive value Not routinely measured Not used to replace imaging techniques

Unknown predictive value Uncertain predictive value

BNP; brain natriuretic peptide; CT: computer tomography; cTnT: cardiac troponin; DMI: Doppler myocardial imaging; E/A: mitral inflow pattern early/atrial ratio; EB: endomyocardial biopsy; ECG: electrocardiography; ECHO: echocardiography; LVEF: left ventricular ejection fraction; MRI: magnetic resonance imaging; MUGA: radionuclide ventriculography multiple-gated acquisition scan.

While guidelines are under development, a number of recommendations have been proposed to manage cardiotoxicity in early breast cancer (Martin et al., 2009; Jones et al., 2009a). Fig. 3 provides a synopsis of patient management in the adjuvant setting, based on a multidisciplinary proactive approach involving cardiologists and oncologists. This concept of teamwork is of paramount importance and should be strengthened for new targeted agents (van Heeckeren et al., 2006; Lenihan, 2008; Lenihan & Esteva, 2008). A close interdisciplinary collaboration allows the early identification of cardiac events, supports a favorable management and provides effective patient care.

5. Perspectives and concluding remarks Anticancer drugs, especially targeted drugs, have brought about many radical changes in oncology, but there is still inadequate understanding to predict, prevent and reduce the occurrence of cardiotoxicity. Basic and clinical studies should address a number of open issues (Gianni et al., 2008). From a pharmacological perspective, the eventual understanding of the primary mechanisms responsible for cardiotoxicity is mandatory. As recommended by many experts of the field (Gianni et al.,

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Fig. 3. Multidisciplinary approach to monitor cardiac safety of HER2 positive breast cancer patients in the adjuvant setting. This approach takes into account the current state of the art of clinical recommendations for the use of trastuzumab [see also (Jones et al., 2009a)]. LVEF: left ventricular ejection fraction; CT: chemotherapy; CHF: chronic heart failure. # Standard medical treatment includes: ACE inhibitors, diuretics, β-blockers. ⁎In case of restart of treatment after any discontinuation due to LVEF abnormalities, LVEF should be assessed every 4 weeks.

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2008; Menna et al., 2008), there is an urgent need to elucidate pathways and targets even for “old-fashioned” chemotherapeutics such as anthracyclines. Specifically, we should move beyond the oxidative stress hypothesis and explore long-term cardiac effects. The effects on non-myocyte cardiac cells should also be evaluated in order to detect early (subclinical) and reversible signs of cardiac damage. In the past, most efforts were aimed at developing highly specific drugs acting on a single kinase. Now, there is a general agreement that promiscuous molecules interfering with multiple targets (e.g. angiogenesis, apoptosis, cancer progression) might be more effective than the single “magic bullet” (Zhang et al., 2008; Fernandez et al., 2009b). With the recent FDA approval of multitargeted inhibitors sorafenib and sunitinib a different scenario has emerged, where a new generation of anti-cancer drugs, able to inhibit more than one pathway, would probably play a major role. The therapeutic value of promiscuity, indeed, has been reassessed and “magic-shotgun” targeting of multiple proteins might possess, in some instances, a higher therapeutic index than a specific drug. On the other hand, the therapeutic disadvantage pertains to the inhibition of a specific pathway ultimately causing cardiomyocyte death. Thus, a rational control of specificity is mandatory to curb adverse side effects. This goal may be achieved through drug redesign guided by toxicological discoveries. Table 1 shows that each chemotherapeutic agent has typical cardiac effects as well as the ability to potentiate the adverse toxicities of other drugs. The question arises whether or not we are dealing with a class effect (i.e. shared by all agents of a given pharmacological class). Considering cardiotoxicity as a class effect seems speculative because it is uncommon with drugs targeting the EGFR: each drug should be evaluated on a case-by-case basis. Significant differences in the clinical setting have recently been evidenced for sorafenib and sunitinib (Wong & Jarkowski, 2009). From the clinical perspective, there is an urgent need to define clinical endpoints of cardiotoxicity and to harmonize cardiac monitoring. Likewise, a risk stratification based on host- and drug-related risk factors will allow a case-by-case approach to treat each patient at the individual level. Moreover, it should be kept in mind that different targeted drugs may act in a synergistic way, thus increasing the likelihood of cardiotoxicity or impairing the clinical phenotype. A critical point regards the invisible part of the iceberg: the rate of cardiac dysfunction associated with TKIs is currently unknown for several reasons. With few exceptions (e.g. trastuzumab and lapatinib), prospective cardiac evaluation during clinical trials was not carried out and the identification of cardiac endpoints was predominantly based on the occurrence of clinical symptoms such as dyspnoea, chest pain and dizziness, which may be unreliable indicators in tumor patients. The long-term risk of cardiotoxicity in clinical practice, where characteristics of patients clearly differ from that in clinical trials (e.g. presence of comorbidities, risk factors, borderline cardiac parameters), adds a further dimension to the scenario and hints at a possible underestimation of the risk, as recently postulated (Schmidinger et al., 2008). The balance between therapeutic gain (in terms of life expectancy) and risk of cardiotoxicity should be evaluated, taking into account the possible impact of genetic background as recently suggested (Beauclair et al., 2007; Zhang et al., 2009). Combining results from clinical and pharmacovigilance studies may provide the basis to implement specific guidelines for these patient subgroups. In conclusion, anticancer drug-induced cardiotoxicity should be viewed as a multifaceted issue: we support a multidisciplinary approach encompassing basic science, oncological and cardiological expertise to mitigate cardiovascular risks associated with chemotherapy.

Acknowledgment This work was supported by a grant from the University of Bologna (Progetto Strategico 2006).

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