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Journal of Clinical Medicine Review Management of Cardiac Toxicity Induced by Chemotherapy Dario Trapani 1, Paola Zagami 1,2, Eleonora Nicolò 1,2, Gabriella Pravettoni 1,2 and Giuseppe Curigliano 1,2,* 1 European Institute of Oncology, IRCCS, 20141 Milan, Italy; [email protected] (D.T.); [email protected] (P.Z.); [email protected] (E.N.); [email protected] (G.P.) 2 Department of Oncology and Hematology (DIPO), University of Milan, 20122 Milan, Italy * Correspondence: [email protected] Received: 21 July 2020; Accepted: 4 September 2020; Published: 7 September 2020 Abstract: Cardiotoxicity encompasses a spectrum of adverse cardiological effects experienced by cancer patients during and after receiving antineoplastic treatments. The intersection of cancer care with the management of the multiple comorbid non-communicable diseases carried by patients or related to cancer treatments motivates the need for an integrated and multidisciplinary approach to therapeutic clinical decision-making. This present review aimed to provide a perspective and an update of the current pharmacotherapy approaches for the prevention and management of cardiotoxicity from antiblastic chemotherapy; as such, it addresses myocardial, vascular, and arrhythmic disorders associated to chemotherapy, by navigating the current knowledge and clinical indications in support of the medical interventions. Clinical scenarios of pharmacological interventions take place with patients receiving anthracycline and, by extrapolation, other agents with cardiotoxic potentials and non-chemotherapy agents, including various small molecules and immunotherapy agents. Analysis of these scenarios aims to provide practical evidence-based guidance for the management of drug-induced cardiac dysfunctions. The possible role of new biomarkers for the early recognition of cardiotoxicity is mentioned across the clinical studies, with reference to the pharmacological biomarker-driven interventions delivered. To best inform survivorship care, the management and context of cardio-oncology services are discussed within the broader network of providers and settings of care. Keywords: cardiotoxicity; chemotherapy; cardio-oncology; treatment-related adverse events; pharmacotherapy 1. Introduction The improvement of early diagnosis and timely cancer treatments has resulted in an improvement of the cancer survival rate in the last decade, with a growing population of cancer survivors. Cancer survivors can carry a multitude of treatment-related comorbidities, including cardiovascular toxicities [1]. As a consequence of treatments, cardiac and vascular pathological conditions can arise de novo from identifiable causal therapeutic agents or emerge for clinical consideration as a worsening of a previously known comorbidity. The presence of comorbidities has a prominent prognostic significance for cancer patients, independently affecting the survival outcomes [2,3]. However, the quality of data used to guide the clinical decisions regarding the appropriate clinical strategies of prevention and control of the cardiovascular sequelae in cancer survivors is still scarce and is widely based on experts’ consensus. This motivates the urgent need for research in cardio-oncology. This present review aims to discuss key points for the management of patients treated with chemotherapy agents and experiencing one or more cardiovascular treatment-related toxicities at some point during the J. Clin. Med. 2020, 9, 2885; doi:10.3390/jcm9092885 www.mdpi.com/journal/jcm J. Clin. Med. 2020, 9, 2885 2 of 18 J. Clin. Med. 2020, 9, x FOR PEER REVIEW 2 of 19 care process.related toxicities The scheme at some used point in during the presentthe care proc workess. isThe based scheme on used the in following the present tripartitework is based approach for cardiovascularon the following disease tripartite description approach for and cardiovasc reporting:ular disease alterations description of and the reporting: contractile alterations myocardium, insufficiencyof the contractile of the vascular myocardium, supply, insufficiency and electric of the heart vascular disorders. supply, The and toxicityelectric heart caused disorders. by anti-vascular The toxicity caused by anti-vascular and targeted agents or immune agents are outside the primary scope and targeted agents or immune agents are outside the primary scope of this review and will only be of this review and will only be briefly mentioned, addressing the analogies and divergencies with briefly mentioned,chemotherapy addressing (Figure 1). the analogies and divergencies with chemotherapy (Figure1). Figure 1.FigureThe spectrum1. The spectrum of cardiac of cardiac toxicity toxicity and theand mostthe most common common related related causative causative antineoplastic antineoplastic agents. agents. 2. The Setting for the Management of Chemotherapy-Related Cardiotoxicity 2. The Setting for the Management of Chemotherapy-Related Cardiotoxicity Cancer health providers are generally aware of the acute onset of the cardiovascular toxicities Cancer health providers are generally aware of the acute onset of the cardiovascular toxicities relatedrelated to chemotherapeutics to chemotherapeutics or selectedor selected monoclonal monoclonal antibodies antibodies and and small small molecules, molecules, and to andsome to some extent, ofextent, the myocardialof the myocardial effects effects from from immunotherapy immunotherapy agents. agents. However, However, thethe management of oflong- long- term sequelaeterm is often sequelae transferred is often totransfe therred primary to the health primary setting health (PHS) setting [4– 8(PHS)]. A multitude[4–8]. A multitude of cardiovascular of sequelaecardiovascular can emerge assequelae clinically can relevantemerge as entities clinically during relevant or beyondentities during the temporal or beyond window the temporal of a standard follow-up,window generally of a standard between follow-up, 5 and 10 generally years after between the cancer5 and 10 treatment years after completion the cancer [treatment9]. The current completion [9]. The current international guidelines for the estimation of cardiovascular risk international guidelines for the estimation of cardiovascular risk generally do not account for the history generally do not account for the history of cancer and the receipt of previous treatments, such as of cancerchemotherapies and the receipt (i.e., oftype previous and exposure) treatments, and radiation such as therapy chemotherapies (i.e., volume (i.e., and typedose) and[10,11]. exposure) and radiationTherefore, therapy the development (i.e., volume of an andadjustable dose) tool [10 ,that11]. is Therefore, ready for clinical the development utilization to better of an tailor adjustable tool thatthe is needs ready of for cancer clinical patients utilization for the toscreening better an tailord prevention the needs of ofthe cancer cardiovascular patients spectrum for the screeningof and preventiondiseases, framed of the cardiovascularin a comprehensive spectrum approach, of diseases,is urgently framed required in a[12]. comprehensive Furthermore, the approach, is urgentlyidentification required of [12 patients]. Furthermore, at higher risk the to identification experience cardiac of patients toxicities at or higher develop risk long to term experience sequelae cardiac is a healthcare priority, which requires an approach that involves the continuum of care and a toxicitiespluralistic or develop dialogue long between term clinicians sequelae from is a the healthcare referring PHS priority, to specialistic which care requires [13]. an approach that involves the continuum of care and a pluralistic dialogue between clinicians from the referring PHS to specialistic3. Principles care [13 of]. Treatment of the Chemotherapy-Induced Cardiotoxicity 3. Principles3.1. Prevention of Treatment of Cardiovascular of the Chemotherapy-InducedDamage Cardiotoxicity 3.1. PreventionPatients of Cardiovascular with no baseline Damage cardiovascular impairment, no increased risk for cardiovascular events, and a conserved left ventricular ejection fraction (LVEF) can benefit from primary preventive Patientspharmacotherapeutic with no baseline interventions cardiovascular [14]. Primary impairment, prevention nowith increased antidotes against risk for cardiotoxic cardiovascular events, and a conserved left ventricular ejection fraction (LVEF) can benefit from primary preventive pharmacotherapeutic interventions [14]. Primary prevention with antidotes against cardiotoxic agents has been proposed in the past, particularly when patients are exposed to high doses of cardiotoxic agents. Anthracyclines are the most prominent cancer treatment agents that cause heart damage, which is expressed mainly, but not exclusively, as left ventricular dysfunction, especially in the symptomatic stage of the damage [15]. The benefit of anthracyclines in some tumors, for example, lymphoma, leukemia, J. Clin. Med. 2020, 9, 2885 3 of 18 and breast cancer, has been thoroughly established but the onset of cardiac toxicity or cardiological contraindications for anthracyclines can result in a poorer oncological outcome, which emphasizes the need to maintain the treatment intensity while ensuring the safest delivery for patients [16]. The most common pattern of toxicity from anthracyclines is cumulative, dose-dependent, and not reversible [17]. Studies on a large mix of cohorts of cancer patients have reported cardiotoxicity occurring in 1 patient
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