Cardiac Complications of Chemotherapy: Role of Prevention

Curr Treat Options Cardio Med (2014) 16:313 DOI 10.1007/s11936-014-0313-6 Cardio-oncology (S Francis, Section Editor) Cardiac Complications of Chemotherapy: Role of Biomarkers Alessandro Colombo, MD1,* Maria T. Sandri, MD2 Michela Salvatici, DSc 2 Carlo M. Cipolla, MD1 Daniela Cardinale, MD, PhD, FESC 3 Address *,1Cardiology Division, European Institute of Oncology, I.R.C.C.S., Via Ripamonti 435, 20141 Milan, Italy Email: [email protected] 2 Laboratory Medicine Division, European Institute of Oncology, I.R.C.C.S., Milan, Italy 3 Cardioncology Unit, European Institute of Oncology, I.R.C.C.S., Milan, Italy * Springer Science+Business Media New York 2014 This article is part of the Topical Collection on Cardio-oncology Keywords Cancer therapy I Cardiotoxicity I Biomarkers I Troponin I Natriuretic peptides dysfunction I Heart failure I ACEI I Beta-blockers I Prevention I Treatment I Left ventricular Abbreviations CT chemotherapy I LVEF left ventricular ejection fraction I MUGA radionuclide multi-gated acquisition I NP natriuretic peptides I cTnI cardiac troponin I I cTnT cardiac troponin T I HF heart failure I AC anthracycline I LVD left ventricular dysfunction I HS highly sensitive I NT-proBNP N-terminal pro-brain natriuretic peptide I CMP cardiomyopathy I ACEI angiotensin-converting enzyme inhibitor I BB beta-blocker Opinion statement Both conventional and novel antineoplastic drugs may cause damage to the heart, ultimately affecting patients’ survival and quality of life. In fact, the most frequent and typical clinical manifestation of cardiotoxicity, asymptomatic or symptomatic left ventricular dysfunction, may be induced not only by conventional cancer therapy, like anthracyclines, but also by new antitumoral targeted therapy such as trastuzumab. At present, left ventricular ejection fraction assessment represents the main standard practice for cardiac monitoring during cancer therapy, but it detects myocardial damage only when a functional impairment has already occurred, not allowing for early preventive strategies. In the last decade, a newer approach based on the measurement of cardiospecific biomarkers has been proposed, proving to have higher prognostic value than imaging modalities. In particular, cardiac troponin elevation during chemotherapy allows us to identify patients who are more prone to develop myocardial dysfunction and cardiac events during follow up. In these pa- 313, Page 2 of 13 Curr Treat Options Cardio Med (2014) 16:313 tients, the use of an angiotensin-converting enzyme inhibitor, such as enalapril, has shown to be effective in improving clinical outcome, giving the chance for a cardioprotective strategy in a selected population. Introduction Currently, the detection of chemotherapy (CT)-induced cardiotoxicity relies on regular assessment of cardiac function by means of left ventricular ejection fraction (LVEF) measurement using either transthoracic echocardiography or radionuclide multi-gated acquisition (MUGA) [1, 2]. However, evidence-based guidelines specifying how often, by what means, or how long cardiac function should be monitored, are lacking. Furthermore, the main limitation of this approach is its low sensitivity for detecting cardiotoxicity at an early stage, because no considerable change in left ventricular systolic function occurs until a critical amount of myocardial damage has taken place. In fact, cardiac damage is usually detected only after functional impairment has already occurred, precluding any chance of preventing its development [3–5]. On the other hand, the evidence of a normal LVEF does not exclude the possibility of a late cardiac deterioration given the low predictive value of LVEF assessment, even when serially repeated. Over the last decade, the use of cardiac biomarkers has been investigated as a possible new approach aimed at early identification, assessment and monitoring of CT-induced cardiotoxicity. This kind of approach offers the advantages of being minimally invasive, low-cost, easily repeatable, without irradiation of the patients, and without interobserver variability. Most of the existing data regarding use of cardiac biomarkers during CT refer to troponins, which are directly reflective of cardiomyocyte integrity, and natriuretic peptides (NP), which are released from the heart in response to volume expansion and increased wall stress. Cardiac troponin in the diagnosis of cardiotoxicity Cardiac troponins are part of a three-unit complex (troponin I, T and C) located on the actin filament and are integral to cardiac muscle contraction. Cardiac troponin I and T (cTnI, cTnT) are sensitive, specific biomarkers of myocardial damage; troponin C is not cardiac-specific—it is shared by slow-twitch skeletal muscles—and is, therefore, not used to diagnose cardiac injury. Cardiac troponins I and T are well-established biomarkers of ischemic heart disease and are the preferred tests for suspected myocardial infarction [6]. However, their use has been extended to detect cardiac damage in other clinical settings, such as LV hypertrophy, heart failure (HF), acute pulmonary embolism, blunt trauma, sepsis, stroke, renal insufficiency and cardiotoxicity associated with CT drugs [7, 8]. Lipshultz et al. [9] showed that TnT increased in about 30 % of cases in children treated with doxorubicin for acute lymphoblastic leukemia and that the magnitude of TnT elevation predicted left ventricular dilatation and wall thickness. More recently, in the same population followed up for 5 years after treatment, the authors reported that children with at least one rise in TnT during CT showed significant late cardiac abnormalities at echocardiography [10, 11]. Several studies are available regarding cardiac troponin elevation Curr Treat Options Cardio Med (2014) 16:313 Page 3 of 13, 313 during CT in adult populations [12–23, 24•]. Data from our group showed that TnI is a sensitive and specific marker of CT induced myocardial injury in 204 adult patients treated with high-dose CT, and is able to predict, in a very early phase, the development of future left ventricular dysfunction (LVD), as well as its severity [12]. Troponin measurements were performed before, immediately after, and then 12, 24, 36, and 72 h after each cycle of CT. Out of the 204 patients, 65 (32 %) showed a positive TnI at 112 of the 661 administered chemotherapy cycles. Approximately half of the elevations were observed at less than 12 h, the remaining elevations occurred 12 to 72 h after CT. In patients showing an increase in TnI, we observed a significant reduction in LVEF from baseline at three months, and LVEF impairment was still evident at the end of the follow-up. Among these patients, 19/65 (29 %) experienced a decline in LVEF to less than 50 %. Patients with normal values of TnI had a transient decrease in LVEF after 3 months, but recovered to an LVEF greater than 50 % afterwards [12]. In a larger study, we enrolled 703 patients with various malignancies in whom TnI was determined before CT, during the 3 days after the end of CT (early evaluation) and after 1 month (late evaluation) [17]. Echocardiography was performed at baseline, 1, 3, 6, and 12 months after the end of each cycle, and every 6 months thereafter or whenever required clinically. Three different troponin release patterns were identified. TnI was consistently within the normal range in 70 % of cases, increased only at early evaluation in 21 %, and increased at both early and late evaluations in 9 %. Patients without TnI elevation after CT showed no significant reduction in LVEF and had a good prognosis, with a low incidence of cardiac events (1 %) during the more than 3-year follow-up. In contrast, TnI-positive patients had a greater incidence of major adverse cardiac events. In particular, among TnI-positive patients, the persistence of the TnI elevation 1 month after CT was consistent with greater cardiac impairment and a higher incidence of events compared with patients showing only a transient increase in the marker (84 % vs. 37 %; pG0.001). In consideration of the high negative predictive value of troponin (99 %), TnI allows identification of low-risk patients who will not require further cardiac monitoring. In contrast, TnI-positive patients require more stringent surveillance, particularly those showing a persistent TnI increase. Other authors have shown that serial measurement of serum TnT reveals subclinical myocardial damage even in patients treated with a standard dose of anthracycline (AC). Auner et al. [15] reported a TnT increase in 15 % of patients treated with standard doses of AC, with a peak level at around 18 days after therapy. Patients with an elevated TnT level showed a significantly greater absolute decrease in LVEF than those without an elevation in the marker (10 % vs. 2 %; p=0.017). Specchia et al. [18] described a significant LVEF reduction in TnI-positive patients treated with AC for leukemia. Finally, Kilickap et al. [19] observed increased TnT levels in 34 % of patients in the first 3 – 5 days following administration of standard doses of AC; again, this increase was predictive of LVD. More recent studies have analyzed a possible role of troponins in the early detection of cardiac injury in patients undergoing treatment with newer targeted cancer drugs. In a study from our group, TnI was assessed in 251 breast cancer patients treated with trastuzumab [21]. In these patients, TnI 313, Page 4 of 13 Curr Treat Options Cardio Med (2014) 16:313 was able to identify accurately patients at risk of developing LVD and, among them, those who were less likely to recover from cardiotoxicity, despite optimized HF treatment, possibly distinguishing between reversible and irreversible cardiac injury induced by a sequential CT treatment with AC and trastuzumab [25]. In fact, LVD occurred in 62 % of patients showing an increase of TnI during trastuzumab treatment, and in only 5 % of those with normal TnI value (pG0.001). Patients showing an increase of TnI during trastuzumab treatment had a threefold decrease in the chance of recovery from cardiac dysfunction, and had a higher incidence of cardiac events. Schmidinger et al. [22] reported an increase in TnT in 10 % of patients with metastatic renal cancer treated with tyrosine-kinase inhibitor sunitinib or sorafenib. Ninety percent of them showed a following decrease in LVEF or regional contraction abnormalities. Morris et al. [23] showed increased TnI in patients receiving both trastuzumab and lapatinib—a tyrosine-kinase inhibitor—following AC-based CT: the timing of detectable TnI preceded maximum decline in LVEF. Sawaya et al. [24•] have explored a possible role of a new generation of highly sensitive (HS)-troponins in this setting. The authors employed HS-troponins and echocardiographic parameters of myocardial deformation to detect LVD in patients receiving AC, taxanes and trastuzumab. They evaluated global and regional myocardial function by tissue Doppler and strain rate imaging, combined with HS-TnI, at baseline, 3, 6, 9, 12, and 15 months during CT. Decreases in peak longitudinal strain and increases in HS-TnI concentrations, at the completion of the AC treatment, were predictive of subsequent LVD. On the other hand, changes in LVEF, diastolic function, and N-terminal pro-brain natriuretic peptide (NT-proBNP) evaluated at the same time points, were not predictive of later LVD. As an elevation in HS-TnI or a decrease in longitudinal strain was associated with higher sensitivity and specificity compared to each parameter alone, this study suggests that combining biomarkers with the newest echocardiographic techniques may have a greater value in the prediction of cardiotoxicity. All these data suggest that troponin release may allow the identification of subclinical cardiac damage in patients treated with both conventional and newer antineoplastic treatments, possibly representing a final event that is common to different mechanisms underlying the cardiotoxic effect. Still there are some limitations for using this marker in clinical practice and there is not a clear, consistent recommendation for their use in the routine monitoring of cardiotoxicity. In the available literature on this topic there is wide variation in the sampling protocols for the measurement of troponins, with increased levels detected at various time intervals after chemotherapy, possibly because of diverse troponin release kinetics in response to cardiotoxic injury with different agents [9, 12, 14, 15, 17–19, 26]. Thus, currently, most research surveillance protocols have deemed it necessary to collect blood samples several times to document a potential increase in troponin levels [27, 28•]. Furthermore, the time-point at which a negative troponin value reaches 100 % of specificity for no further troponin release still cannot be defined [29]. However, measurement of troponin only immediately before and immediately after each cycle of cancer therapy seems to be effective enough, and is also transferable from clinical research to daily clinical practice [21]. This protocol appears to be cost-effective when negative values Curr Treat Options Cardio Med (2014) 16:313 Page 5 of 13, 313 allow for the exclusion of most patients from a long-term monitoring program with more expensive imaging modalities. Standardization of routine troponin measurement in the clinical setting to maximize single-time-point assay sensitivity and specificity is needed and should be an important focus for future research. Furthermore, additional vascular biomarkers, such as endothelial growth factors, may be important in identifying those patients at risk for vascular toxicity with newer antiangiogenic-based treatment, although, currently available data are only speculative [30•]. Natriuretic peptides in the diagnosis of cardiotoxicity The NP are cardiac neurohormones that are released from the atrial and ventricular myocardium in response to increased wall stress: atrial natriuretic peptide (ANP) and its amino-terminal fragments (NT-proANP) are released primarily from the atria; brain natriuretic peptide (BNP) and its N-terminal fragments (NT-proBNP), are predominantly released from the ventricular cardiomyocytes. They are involved in many physiologic functions including vasodilation, natriuresis, kaliuresis, inhibition of the reninangiotensin-aldosterone system and inhibition of sympathetic tone. BNP and NT-proBNP, whose half-life is much longer than that of ANP in humans, are gaining acceptance as biomarkers potentially useful in the diagnosis and prognostic stratification of patients with HF [31, 32]. Several studies have explored a role for natriuretic peptides in the detection and prediction of cardiotoxicity induced by CT. After a first report by Suzuki et al. [33], showing that persistent elevations of BNP were associated with reduced cardiac tolerance to cardiotoxic agents in 27 patients with hematologic malignancy, multiple articles were published about patients with different malignancies (hematologic and solid tumors) and different ages (children and adults), and oncologic treatment [34–56]. Although most of the studies showed an association between increased levels of NP and cardiac dysfunction, only few reports indicated NP as predictors of LVD after CT [40, 43, 54]. Data from our institution showed that persistent high plasmatic levels of NTproBNP were able to identify patients who will develop an impairment of both diastolic and systolic function 1 year after CT [40]. Three distinct NT-proBNP concentration patterns were found. Thirty-one percent of patients had no changes in NT-proBNP concentrations during the six samples taken in the 72 h after CT; 35 % of patients had only a transient increase, with concentrations normalizing at 72 h. In all these patients, no significant echocardiographic changes were recorded during follow-up. Thirty-three percent of patients with persistently increased NTproBNP concentrations at 72 h developed a significant worsening of both diastolic and systolic properties values during the 12 months of observation. In particular, the echocardiographic monitoring revealed significant increases in mitral deceleration time, in isovolumetric relaxation time and in mitral E/A ratio. LVEF mean value decreased from 62.8 % to 45.6 % (pG0.001). A strong relationship between NT-proBNP value at 72 h, and LVEF changes at 12 months versus baseline was found. Other recent reports are consistent with these findings, showing a close relationship between NP and the development of subclinical myocardial injury due to the administration of chemotherapy [34, 43, 48, 53–56]. However, only a few 313, Page 6 of 13 Curr Treat Options Cardio Med (2014) 16:313 studies found no correlation between NT-proBNP increase and development of cardiac dysfunction in patients receiving AC-based CT [20, 24•, 47]. Therefore, although several data are now available, it is not yet possible to draw definite conclusions or indications for the clinical practice because of some important limitations that make the comparison of the results coming from the different studies quite difficult. First, most studies enrolled small populations of patients with a large heterogeneity (different malignancies at various stages, use of different CT regimens). Furthermore, different laboratory methods were used, with frequently undeclared cutoffs, an extremely broad range of sampling times among the studies and the lack of standardized cardiac endpoints. Finally, the follow-up duration of the studies was quite variable and sometimes too short [29]. New prospective and multi-center studies, including large populations, using well-standardized methods for dosage and with well-defined timing of sampling and cardiologic end-points, are needed to define the appropriate use of NP in this setting. Prevention of cardiotoxicity Several preventive measures to reduce the risk of cardiotoxicity have been proposed, including limiting cumulative CT dose, altering AC administration, using less cardiotoxic AC analogues. However, the addition of cardioprotectants and detection of early signs of cardiotoxicity by biomarkers are the two most promising strategies [57–59]. Adding cardioprotectants to AC treatment Dexrazoxane, an iron-chelating agent, is associated with a reduction of AC-related cardiotoxicity in adults with different solid tumors and in children with acute lymphoblastic leukemia and Ewing’s sarcoma [10, 60, 61]. Moreover, in a recent study, Huh et al. reported that dexrazosane may be more favorable in preventing AC-related cardiotoxicity when compared to AC prolonged infusion [62]. Dexrazoxane is not routinely used in clinical practice and it is recommended as a cardioprotectant by the American Society of Clinical Oncology, only in patients with metastatic breast cancer who have already received more than 300 mg/m2 of doxorubicin [63]. This might be explained by the suspicion of interference with antitumor efficacy of AC, and by the occurrence of secondary malignancies, as well as by its possible myelosuppressor effect. However, meta-analyses of antitumor efficacy and of occurrence of secondary malignancies did not find a significant difference between patients who were treated with or without dexrazoxane [57, 61, 64, 65]. Carvedilol is a beta-blocker with alpha-1-blocking vasodilatory properties, whose potent antioxidant activity may be the mechanism underlying its cardioprotective effect against doxorubicin [58]. The cardioprotective effect of carvedilol was shown in an in vitro study [66], and in a randomized study in which prophylactic use of carvedilol in a small population of patients treated with AC prevented cardiomyopathy (CMP) and reduced mortality [67]. A protective effect against AC-induced CMP of another beta-blocker, nebivolol, has been demonstrated in a recent randomized study. In 27 patients receiving nebivolol during AC-therapy, LVEF and NT-proBNP Curr Treat Options Cardio Med (2014) 16:313 Page 7 of 13, 313 remained unchanged after 6 months from baseline; conversely, in the placebo group, a significantly lower LVEF and a higher NT-proBNP value were observed [68]. In the OVERCOME trial, Bosch et al. [69] explored the efficacy of enalapril and carvedilol to prevent chemotherapy-induced LVD in 90 patients with various hematologic malignancies receiving intensive high-dose chemotherapy. Patients were randomized to the intervention group (enalapril plus carvedilol; n=45) or the control group (no cardiovascular drugs; n=45). LVEF was measured before and after chemotherapy using cardiac magnetic resonance and echocardiography. After 6 months, LVEF had not changed in the intervention group, but it had decreased significantly in the control group. Larger studies are needed to confirm the clinical relevance of this approach. Other cardioprotective agents like coenzyme Q10, carnitine, Nacetylcysteine, the antioxidant vitamins E and C, erythropoietin, the endothelin-1 receptor antagonist bosentan, the lipid-lowering agent probucol, and statins have been investigated. Preliminary evidence shows that these agents may have cardioprotective effects, but their utility in preventing CMP requires further investigation [57, 59, 61, 70, 71]. Role of cardiac biomarkers A primary pharmacologic preventive strategy extended to all cancer patients undergoing CT has a very high cost–benefit ratio, exposing them to possible side-effects (including a possible antagonistic effect to antitumor activity of CT) who otherwise might be less prone to develop cardiotoxicity and who do not need any cardioprotective therapy. The possibility of identifying patients at higher risk of developing cardiotoxicity by cardiac biomarkers provides a rational alternative directed at counteracting the ongoing myocardial damage and preventing the development of cardiac dysfunction and adverse cardiac events. Two different therapeutic strategies may be implemented to reduce the clinical impact of cardiotoxicity: use of specific cardiologic treatments during CT in the attempt to prevent, or blunt, the rise of these markers; or use of cardiologic treatments given only to selected cancer patients showing an increase in these markers after CT. Nakamae et al. showed, in a randomized trial, that valsartan, an angiotensin 2 receptor blocker, given at the same time as AC-containing CT, prevents increase in atrial natriuretic peptide and brain natriuretic peptide, acute increase in left ventricular diastolic diameter, and prolongation and dispersion in QTc interval, in a small population [42]. Lipshultz et al. [60] reported that TnT elevation occurred significantly more frequently in leukemic children receiving doxorubicin alone than in children in whom doxorubicin was administered in association with dexrazoxane (50 % vs. 21 %, respectively; p=0.001). The possible role of telmisartan in preventing myocardial damage induced by epirubicin was investigated in a randomized study including 49 patients free of cardiovascular diseases and treated with epirubicin for a variety of solid cancers. After up to 18-month follow-up, 25 patients starting telmisartan 1 week before epirubicin showed no significant reductions in myocardial deformation parameters (peak strain rate) as evaluated by using tissue Doppler echocardiogram, or any significant increase in reactive oxygen species or in 313, Page 8 of 13 Curr Treat Options Cardio Med (2014) 16:313 interleukin-6, as found in 24 patients receiving only epirubicin [72, 73]. This finding suggests that telmisartan may protect these patients from epirubicininduced radical species production and reduce the generation of inflammation, thus preventing the development of early myocardial impairment. The usefulness of TnI in selecting patients for prophylactic cardioprotective therapy was investigated in a randomized, controlled trial, carried out at our institute [58]. The cardioprotective effects of enalapril were evaluated in 413 patients treated with high-dose AC. The 114 (24 %) patients showing early TnI increase were randomized either to receive the angiotensin converting enzyme inhibitor (ACEI) enalapril (ACEI group, n=56) or not (controls, n=58). Treatment was started one month after CT and was continued for 1 year. Enalapril was well tolerated in most patients; in only one patient who developed a cough, the enalapril dosage was decreased and the symptom resolved. The maximal tolerated dose of enalapril in the ACEI group was 16±6 mg/day. In the ACEI group, LVEF did not change during the follow-up period, whereas, in patients not receiving enalapril, a progressive reduction in LVEF and an increase in enddiastolic and end-systolic volumes were observed (Table 1). Furthermore, patients in the ACEI group had a lower incidence of adverse cardiac events than patients not receiving enalapril (2 % vs. 52 %; pG0.001) (Table 2). The usefulness of TnI monitoring has also been recently demonstrated in patients treated with developing molecular targeted therapies. In a phase I trial, Ederhy et al. [74] observed troponin value increase from baseline during treatment with new anti-VEGF monoclonal inhibitors and tyrosine kinase inhibitors in patients with solid metastatic tumors. All patients showing an increase in the marker underwent echocardiography, cardiac magnetic resonance, CT scan, and coronary angiography that excluded other possible etiologies of TnI increase. Normalization of troponin values was obtained with a treatment by beta-blocker (BB) and aspirin. After TnI normalization, all patients were re-challenged with the study drug. No patient experienced any new increase of TnI, and no cardiac events occurred during the following observation period. The important finding of this study is that TnI can also be used to identify patients more prone to developing cardiotoxicity in the setting of clinical trials, as well as in daily clinical practice. It must be stressed that troponin increase is a warning, not a reason to withdraw the anticancer drug. Therefore, patients with a troponin increase should be treated with a prophylactic therapy against the development of cardiotoxicity, rather than be excluded from continuing oncologic treatment. Table 1. Echocardiographic parameters during the study period. Modified from Cardinale [58] EDV (ml) ESV (ml) LVEF (%) ACEI-group Controls ACEI-group Controls ACEI-group Controls Baseline Rand. 3 months 6 months 12 months P value* 101.7±27.4 103.2±20.1 38.6±10.8 38.8±10.2 61.9±2.9 62.8±3.4 100.2±26.1 103.9±21.0 38.7±10.4 40.5±12.2 61.1±3.2 61.8±4.3 98.1±27.8 106.4±21.0 37.3±10.9 49.8±17.6 61.9±3.3 54.2±8.1 97.5±24.5 107.1±23.9 37.4±10.3 51.8±16.9 61.6±3.9 51.9±7.9 101.1±26.4 104.2±25.6 38.5±11.2 54.4±20.1† 62.4±3.5 48.3±9.3† 0.045 *P value for repeated measures analysis of variance. † = pG0.001 vs. baseline EDV = end-diastolic volume; ESV = end-systolic volume; LVEF = left ventricular ejection fraction; Rand. = randomization G0.001 G0.001 Curr Treat Options Cardio Med (2014) 16:313 Page 9 of 13, 313 Table 2. Cardiac events in the study groups. Modified from Cardinale [58] Sudden death Cardiac death Acute pulmonary edema Heart failure Arrhythmias requiring treatment CUMULATIVE EVENTS Total (n=114) ACEI group (n=56) Controls (n=58) P value 0 (0 %) 2 (2 %) 4 (3 %) 14 (12 %) 11 (10 %) 31 0 0 0 0 1 1 0 (0 %) 2 (3 %) 4 (7 %) 14 (24 %) 10 (17 %) 30 1.0* 0.49* 0.07* G 0.001 0.01 G 0.001 (0 (0 (0 (0 (2 %) %) %) %) %) * = by Fisher exact test Figure 1 reports the algorithm for the management of cardiotoxicity in patients receiving anthracyclines as proposed in the European Society for Medical Oncology Clinical Practice Guidelines latest version [75]. Although not yet validated in large prospective clinical trials, it includes the role of TnI assessment during AC-containing chemotherapy in identifying patients with subclinical cardiotoxicity and their treatment with ACEIs to prevent the development of further left ventricular dysfunction. When this kind of approach is not feasible, a close LVEF monitoring is recommended after the end of chemotherapy and, if left ventricular dysfunction is identified, a prompt treatment with ACEIs, possibly in combination with BBs, is strongly suggested. Conclusion The current standard for monitoring cardiac function during CT detects cardiotoxicity only when a functional impairment has occurred and, thereFigure 1. Algorithm for the management of cardiotoxicity in patients receiving anthracyclines. ACEI = angiotensinconverting enzyme inhibitors; BB = beta-blocking agents; CT = chemotherapy; ECHO = echocardiogram; TnI = Troponin I; LVD = left ventricular dysfunction. Modified from Curigliano et al. [75]. 313, Page 10 of 13 Curr Treat Options Cardio Med (2014) 16:313 fore, does not allow for an early preventive strategy. The best approach for minimizing cardiotoxicity is early detection combined with prompt initiation of prophylactic treatment. The use of a cardioprotectant regimen has been proposed in all patients treated with potentially cardiotoxic cancer drugs. However, a pharmacologic preventive approach extended to all cancer patients undergoing CT may have a very high cost-benefit ratio, also potentially exposing patients less prone to develop cardiotoxicity to possible side effects. A preventive therapy in selected high-risk patients, identified by an increase in cardiac biomarkers, particularly troponin, during and/or after CT, may represent a reasonable alternative. Indeed, a prophylactic treatment with enalapril in patients with an early increase in troponin after CT has been shown to be very effective in preventing LVD and associated cardiac events. Additional work is needed to confirm the potential role of cardiac troponin and to establish the most cost effective sampling protocol. Furthermore, new potential biomarkers for early detection of myocardial cell injury should also be considered and further studies should clarify if a multi-marker approach would permit a better stratification of the cardiac risk and a more effective management of cancer patients treated with CT. Compliance with Ethics Guidelines Conflict of Interest Dr. Alessandro Colombo, Dr. Maria T. Sandri, Dr. Michela Salvatici, Dr. Carlo M. Cipolla, and Dr. Daniela Cardinale each declare no potential conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors. References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance 1. 2. Hunt SA, Abraham WT, Chin MH, et al. Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults. 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