Strategies to Prevent and Treat Cardiovascular Risk in Cancer Patients

Strategies to Prevent and Treat Cardiovascular Risk in Cancer Patients Daniela Cardinale,a Giulia Bacchiani,b Marta Beggiato,a Alessandro Colombo,b and Carlo M. Cipollab Cardiotoxicity due to cancer treatment is of rising concern, for both cardiologists and oncologists, because it may have a significant impact on cancer patient management and outcome. The most typical manifestation of cardiotoxicity is a hypokinetic cardiomyopathy leading to heart failure. However, the spectrum of the toxic effects that can impair the cardiovascular system may also include acute coronary syndromes, hypertension, arrhythmias, and thromboembolic events. Patients undergoing cancer treatment are more vulnerable to cardiovascular injuries, and their risk of premature cardiovascular disease and death is higher than that of the general population. Prevention of cardiotoxicity remains the most important strategy, and several measures, including cardiac function monitoring, limitation of chemotherapy dose, use of anthracycline analogues and cardioprotectants, and early detection of myocardial cell injury by biomarkers, have been proposed. The response to modern heart failure therapy of cancer treatment–induced cardiomyopathy has never been evaluated in clinical trials, and currently there are no definitive guidelines. Although it is likely that medications used for other forms of cardiomyopathy, particularly angiotensin-converting enzyme inhibitors and ␤-blockers, may be highly effective, there is still some unjustified concern regarding their use in cancer patients. Specific guidelines that take cardiologic conditions of cancer patients into account are currently lacking and need to be developed. Semin Oncol 40:186-198 © 2013 Elsevier Inc. All rights reserved.

O

ver the last 2 decades, the survival rate of cancer patients has significantly increased due to improvements in modern cancer therapy, consisting of chemotherapy (CMT), antibody-based therapy, radiation therapy (RT), and surgery.1 To achieve these results, however, a considerable price has been paid in terms of adverse effects associated with intensive oncologic treatment. In particular, cardiotoxicity may compromise the clinical effectiveness of the cancer therapy, independently of the oncologic prognosis, and have an impact on the patient’s survival and quality of life. The most frequent and feared clinical manifestation of cardiotoxicity is the development of left ventricular dysfunction (LVD), leading to congestive heart failure (HF). However, the spectrum of the abnormalities that can impair the cardiovascular aCardioncology

Unit, European Institute of Oncology, Milan, Italy. Division, European Institute of Oncology, Milan, Italy. The authors report no potential conflicts of interest. Address correspondence to Daniela Cardinale, MD, PhD, FESC, Cardioncology Unit, European Institute of Oncology, Via Ripamonti 435, Milan, Italy 20141. E-mail: [email protected] 0270-9295/ - see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminoncol.2013.01.008 bCardiology

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system may include acute coronary syndromes, hypertension, arrhythmias, and thromboembolic events.2 In recent years, the implications of the cardiotoxic effect of anticancer treatment has markedly increased due to improvement in patient survival, ageing of the population (including cancer patients), and the introduction of new cancer drugs with unexpected toxicities. According to estimates from the National Cancer Institute, the Centers for Disease Control and Prevention, and data from Eurocare studies, there are currently more than 11 million cancer survivors, both in the United States and in Europe.3 Many of them have had radiation or cancer treatments, with the potential for long-term cardiovascular toxicity. Hence, a comprehensive and professional management plan aimed at cancer patients whose clinical history and oncologic treatment put them at higher risk for developing cardiovascular problems is needed to counteract the development of adverse events and their early and late sequelae. A new medical discipline, cardio-oncology, has been created to satisfy this demand. The neologism was first introduced into literature in 1996,4 to describe the new field of integrative medicine between cardiologists and oncologists. At present, cardio-oncology is a well-recognized new medical discipline, aimed at developing a Seminars in Oncology, Vol 40, No 2, April 2013, pp 186-198

Prevention and treatment of cardiotoxicity of anticancer agents

close interaction between the two specialties, investigating new strategies, collecting new evidence-based indications, and creating interdisciplinary expertise to better manage this growing category of patients.5–9 The purpose of this review is to focus on the current evidence regarding early detection, prevention and treatment of cardiovascular toxicity induced by anticancer agents.

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Baseline cardiovascular risk factors Cancer diagnosis

Decreased cardiovascular reserve

INCREASE IN CARDIOVASCULAR RISK There is rising evidence that patients previously treated with CMT and RT are at increased cardiovascular risk. The risk of cardiac death in these patients is higher than the actual risk of tumor recurrence,10,11 with a seven-fold higher mortality rate, 15-fold increased rate of HF, 10-fold higher rates of cardiovascular disease, and nine-fold higher rates of stroke than the general population.11 In long-term cancer survivors, a higher incidence of hypertension, dyslipidemia, acute coronary syndromes, and stroke have been reported,12 so much so that the cardiovascular risk associated with CMT has been reported to be similar to that of smoking.13 Baseline risk factors and heart disease being equal, patients previously treated with CMT (especially those treated with anthracyclines [AC]) have been shown to have an increased risk of cardiomyopathy (CMP), HF, and myocardial infarction, in the subsequent 20 years.14 Therefore, CMT should be considered as a novel cardiovascular risk factor, and previous CMTtreated patients should be considered deserving of cardiologic monitoring, just as done with patients who have other traditional cardiovascular risk factors. The more convincing hypothesis is that during their long clinical path, oncology patients are exposed to a series of sequential or concurrent cardiovascular insults, associated with changes in lifestyle.15 Frequently, after diagnosis of cancer, patients stop exercise, have a tendency to increase their body weight, and to develop depression (a newly recognized cardiovascular risk factor).16 These factors together make patients more vulnerable to cardiovascular injuries and increase their risk of premature cardiovascular death (Figure 1).15,17 Importantly, as shown by data from the Chicago Heart Association Detection Project in Industry, a pre-existing cardiovascular risk factor is itself a strong predictor for the development of cardiovascular injury after CMT, making the likely risk for cardiovascular disease much greater.18 Therefore, during the oncologic-active treatment phase, every effort must be made to continue and optimize the therapy of underlying cardiovascular diseases, as well as to correct pre-existing and newly acquired cardiovascular risk factors. In addition, as the mechanisms of particular cardiovascular toxicities in cancer patients may differ from those of the general population, and the presence of cancer may limit therapeutic options, general treatment guidelines in cardio-

Adjuvant therapy (direct effects)

Modifiable lifestyle risk factors (indirect effects)

Higher risk of cardiovascular disease and mortality

Figure 1. The multiple-hit hypothesis. Modified from Jones et al.15

vascular disorders may not be appropriate in cancer patients. Specific guidelines for cancer treatment that take cardiologic conditions into account are currently lacking and need to be developed.

MONITORING OF PATIENTS AT RISK FOR VASCULAR COMPLICATIONS Identification of cancer patients at high risk for cardiovascular events will be one key strategy to reduce morbidity and mortality from cardiovascular toxicity related to cancer therapy. However, at present, recommendations for screening and monitoring of these patients are lacking. Cancer treatment, by inducing endothelial dysfunction and accelerating atherosclerotic processes, leads to an increased risk for future cardiovascular events.13,19 Several clinical studies have investigated endothelial damage in cancer patients. Increased levels of markers of endothelial dysfunction, such as endogenous inhibitors of nitric oxide and asymmetric and symmetric dimethylarginines, have been detected many years after CMT in long-term cancer survivors.20 Therefore, monitoring of these markers or of brachial artery flow-mediated dilation, an established technique to identify endothelial injury, might help in the prediction of cardiovascular events after cancer therapy.21 Other vascular parameters, such as carotid intima-media thickness, might also be used to characterize potential endothelial damage.22 However, adequate, prospective studies should be conducted to validate these markers in this setting.

CMT-INDUCED LVD The most classic and frequent clinical manifestation of cardiotoxicity is the development of LVD. Its devel-

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opment, even when asymptomatic, not only negatively affects patients’ cardiologic outcome, but it also seriously limits their therapeutic opportunities when adjunctive CMT for cancer relapse is required. Indeed, the presence of impaired cardiac function restricts the choice of possible oncologic treatments to those considered less aggressive and, consequently, less effective. According to the American College of Cardiology and American Heart Association guidelines, patients receiving CMT may be considered a stage A HF group; namely, those with an increased risk of developing LVD.23 In the past, this form of LVD has nearly always been associated with cancer treatments, including AC; at present, however, several new cancer drugs have also been shown to induce this complication.1 This form of CMP is believed to be refractory to conventional HF therapy and characterized by an especially poor prognosis, with a reported 2-year mortality rate of about 60%.24 This opinion, however, was based on findings reported in old studies investigating small populations in which standard therapy included only the use of digoxin and diuretics.25,26 Nevertheless, recent data clearly show that the time elapsed from the end of CMT to the beginning of modern HF therapy, including angiotensin-converting enzyme (ACE) inhibitors and ␤-blockers, after the development of LVD is an important determinant of the extent of recovery from CMTinduced CMP.27 This highlights the need for an early and real-time diagnosis of cardiac injury in cancer patients receiving potentially cardiotoxic drugs.

EARLY DETECTION OF CARDIOTOXICITY Current Approach There are currently no evidence-based guidelines for monitoring of cardiotoxicity during and after cancer therapies in adults; guidelines in pediatric oncology are a matter of debate. Several recommendations are available; however, none specify how often, by what means, or how long cardiac function should be monitored.28,29 In current clinical practice, transthoracic echocardiography and multi-gated radionuclide angiography are the most commonly used modalities for noninvasive baseline and serial assessment of left ventricular ejection fraction (LVEF). However, LVEF measurement is essentially a relatively insensitive tool for detecting cardiotoxicity at an early stage, mainly because no considerable change in LVEF occurs until a critical amount of myocardial damage has taken place, and the damage only comes to the forefront after compensatory mechanisms are exhausted. When LVD develops, complete recovery of cardiac function occurs in only 42% of patients, despite optimal pharmacologic therapy.27 Therefore, the diagnosis of cardiotoxicity, based on evidence of a decrease in LVEF, precludes any chance of preventing the development of cardiotoxicity.19

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Conversely, a normal LVEF does not exclude the possibility of later cardiac deterioration. In addition, the measurement of LVEF presents a number of challenges related to image quality, assumption of LV geometry, load dependency, and expertise. Improved accuracy and reproducibility of LVEF measurements is an actual need in patients receiving cancer therapy because clinical decision making relies completely on these measurements. Multi-gated acquisition scans can reduce inter-observer variability; disadvantages include the exposure to radioactivity and the limited information that can be obtained on cardiac structure and diastolic function. Magnetic resonance imaging is considered to be the gold standard for the evaluation of cardiac volumes, mass, and both systolic and diastolic function.30 However, its high cost and lack of availability limit its routine use. More sensitive echocardiographic techniques, such as contrast echocardiography and real-time threedimensional echocardiography (which may identify cardiotoxicity at an earlier, modifiable stage of the disease) are under review. Small studies examining tissue Doppler and strain rate imaging appear promising in detecting early sub-clinical changes in cardiac performance that anticipate a decrease in conventional LVEF, even if long-term data from large populations, confirming the clinical relevance of such changes, are not yet available.30,31

The Role of Biomarkers The limitations of cardiac imaging may be surmounted by the use of cardiac biomarkers. A novel approach, based on the use of troponins, has emerged in the last decade, resulting in a cost-effective diagnostic tool for early, real-time identification and the assessment and monitoring of cancer drug–induced cardiotoxicity. This approach seems to overcome most of the limitations of the techniques described earlier, as it has proven to be more sensitive and more specific, cheaper, repeatable without damage to the patients, readily available even in small hospitals, and without inter-observer variability.

Conventional troponins Cardiac troponin I and T are structural proteins unique to the heart and involved in the contraction– relaxation process; their detection in peripheral blood indicates cardiomyocyte necrosis. Since 2000, cardiac troponins have been defined as the biomarkers of choice for the diagnosis of acute myocardial infarction.32 In addition to acute coronary syndromes, their use has been extended to a wide range of diverse pathologic conditions characterized by cardiac injury, such as LV hypertrophy, HF, pulmonary embolism, blunt trauma, sepsis, stroke, chronic kidney disease, and cardiotoxicity associated with cancer drugs.33 At present, troponins are considered the gold standard mark-

Prevention and treatment of cardiotoxicity of anticancer agents

A

B

TnI (ng/ml) 0

70

0

*

60

TnI-positive

55

† † 1

2

3

† 4

0.5

1.0

1.5

2.0

2.5

-10 -20 -30 -40

r = -0.87

P <.0001

-50

50 0

ΔLVEF (%)

TnI-negative

65

LVEF (%)

189

-60 7

Months

Figure 2. (A) Left ventricular ejection fraction (LVEF) at baseline and during the 7-month follow-up in troponin I (TnI)-positive and TnI-negative patients. *P ⬍.001 versus baseline (month 0); †P ⬍.001 versus the TnI-negative group. (B) Scatterplot of LVEF changes against TnI value in TnI-positive patients. Modified from Cardinale et al.40

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 CMT was consistent with greater cardiac impairment and a higher incidence of events compared with patients showing only a transient increase in the marker (84% v 37%; P ⬍.001). Thanks to its high negative predictive value (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. Troponin measurements also have proven to be useful for the early detection of cardiotoxicity in patients

‡ 0.8 0.7

*†

0.6

TnI (ng/ml)

ers for myocardial injury from any cause.34 In addition to the nearly absolute cardiac tissue specificity, troponins have a high sensitivity for detecting small amounts of necrosis, not allowed by less-sensitive biomarkers such as creatine kinase and its myocardial band iso-enzyme. In all clinical settings, troponins not only allow for detection of myocardial injury but also for cardiac risk stratification, as their elevation correlates with clinical severity of the disease and cardiac outcome.35 The role of cardiac troponins as indicators of early AC-induced cardiotoxicity and their ability to predict subsequent myocardial dysfunction has been studied in animal models.36,37 In children treated with AC for lymphoblastic leukemia, Lipshultz et al38 reported a troponin T (TnT) increase in about 30% of cases, sometimes persisting for months, suggesting that cardiac damage, elicited by AC, may last for a long time. TnT increase positively correlated with AC dose, and predicted morbidity and mortality. More recently, in the same population followed up for 5 years after treatment, the authors observed that children who had experienced at least one increase in TnT during CMT showed late cardiac abnormalities at echocardiography.39 Further studies have demonstrated that troponin I (TnI) is also a sensitive and specific marker for myocardial injury in adults treated with high-dose CMT, and it is able to predict, at an early phase, both development and severity of future LVD (Figure 2).40 – 42 The largest study was performed in 703 patients with cancer, in whom TnI was determined before CMT, during the 3 days after the end of CMT (early evaluation), and after 1 month (late evaluation).43 Three different troponin release patterns were identified. TnI was consistently within the normal range in 70% of cases, increased at only early evaluation in 21%, and increased at both early and late evaluations in 9% (Figure 3). Patients without TnI elevation after CMT showed no significant reduction in LVEF and had a good prognosis, with a low incidence of cardiac events (1%) during the

0.5 0.4 0.3 TnI +/+ 0.2 0.1

0.0

TnI +/–

†

TnI –/–

Early TnI (ng/ml)

§ Late TnI (ng/ml)

Figure 3. Early and late troponin I (TnI) values in the three study groups. TnI ⫹/⫹ (n ⫽ 63; 9%); TnI ⫹/– (n ⫽ 145; 21%); TnI –/– (n ⫽ 495; 70%). *P ⬍.001 versus TnI ⫹/–. †P ⬍.001 versus TnI –/–. ‡P ⬍.05 versus early TnI. §P ⬍.001 versus early TnI. Modified from Cardinale et al.43

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Table 1. Major Adverse Cardiac Events in the Whole Population and in Patients Stratified According to

Elevation of Troponin I During Trastuzumab Therapy Event

Total (N ⴝ 251)

Elevated Troponin I (n ⴝ 36)

Normal Troponin I (n ⴝ 215)

Severe LVEF reduction (ⱕ30%) Cardiac death Acute coronary syndrome Acute pulmonary edema Heart failure Arrhythmias requiring treatment Cumulative events

7 (3) 0 (0) 2 (1) 1 (⬍0.5) 7 (3) 5 (2) 22 (9)

6 (17) 0 (0) 2 (6) 1 (3) 7 (19) 2 (8) 18 (50)

1 (0.5) 0 (0) 0 (0) 0 (0) 0 (0) 3 (1) 4 (2)*

All values are given as no. (%). Modified from Cardinale et al.47 Abbreviation: LVEF, left ventricular ejection fraction. *P ⬍0.001 versus elevated troponin I (according to the Fisher exact test).

treated with a standard dose of CMT. Auner et al44 reported a TnT increase in 15% of patients treated with standard doses of AC. Patients with an elevated TnT level showed a significantly greater absolute decrease in LVEF than those without an elevation in the marker (10% v 2%; P ⫽ .017). A significant LVEF reduction was observed in TnI-positive patients treated with AC for leukemia.45 In addition, an increased TnT level, detected in the first 3–5 days after administration of standard doses of AC, predicted diastolic dysfunction in 34% of patients.46 Troponins also may be used to identify early cardiac injury in patients undergoing treatment with newer targeted cancer drugs. The role of TnI also has been studied in 251 breast cancer patients treated with trastuzumab.47 TnI was measured immediately before and immediately after each cycle, and it increased in 14% of patients. LVD occurred in 62% of them and in only 5% of patients with a normal TnI value (P ⬍.001). Patients displaying an increase in TnI during trastuzumab treatment had a three-fold lower chance of recovery from cardiac dysfunction and an overall higher incidence of cardiac events (Table 1). In this study, therefore, TnI was able to accurately identify patients at risk of developing LVD and, among them, those who will less likely recover from cardiotoxicity, despite optimized HF treatment, thus possibly distinguishing between reversible and irreversible cardiac injury. More recently, Morris et al48 also demonstrated that TnI values increase in patients receiving both trastuzumab and the tyrosine kinase inhibitor lapatinib preceded by AC-based CMT. The timing of maximum detectable TnI value preceded maximum decline in LVEF. In 86 patients with metastatic renal cancer treated with the tyrosine kinase inhibitor sunitinib or sorafenib and monitored prospectively with serial TnT measurements, the increase in the marker was observed in 10% of patients. 49 Ninety

percent of them showed a decrease in LVEF or regional contraction abnormalities. These data suggest that troponins may be useful for assessing cardiotoxicity in patients treated with both conventional and newer cancer therapies. Possibly, the release of troponin reflects a final common event for multiple cardiotoxic mechanisms.

High-sensitivity troponins Recent advances in assay technology have led to more sensitive and precise troponin assays. These new high-sensitivity (HS) assays can now reliably measure small elevations that are undetectable by using other troponin assays.50 These tests could be of particular interest and offer some advantages in the field of cardiotoxicity, as we often deal with low concentrations of troponin, and it is of the utmost importance to use high-precision systems at low concentration levels. The possible use of HS troponins in this setting was presented by Sawaya et al51 in a recent multicenter study. The authors used 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 using tissue Doppler and strain rate imaging, combined with HS TnI, at baseline and 3, 6, 9, 12, and 15 months during CMT. Decreases in peak longitudinal strain and increases in HS TnI concentrations at the completion of the AC treatment were predictive of subsequent LVD. Conversely, changes in LVEF, diastolic function, and N-terminal pro–B-type natriuretic peptide (NTproBNP), a hormone secreted by the atria and ventricles in response to increased wall stretch,52 evaluated at the same time points were not predictive of later LVD.51 Further studies are needed in larger populations with longer follow-up to define the predictive accuracy

Prevention and treatment of cardiotoxicity of anticancer agents

of these echocardiographic parameters and to compare HS troponins with traditional troponin assays in identifying patients who will develop LVD.

PREVENTION OF CARDIOTOXICITY Current Possible Strategies Several approaches to protect the heart from cardiotoxicity have been proposed, including limitation of cumulative AC dose, slowing down of AC administration, and use of fewer cardiotoxic AC analogues. However, the addition of cardioprotectants and detection of early signs of cardiotoxicity by biomarkers are the two most promising strategies.31,53,54

Addition of Cardioprotectants to AC Treatment Carvedilol, a ␤-blocker with ␣1-blocking vasodilatory properties, also has shown strong anti-oxidant activity that lends it a cardioprotective effect against doxorubicin.53 This favorable effect was confirmed in an in vitro study55 and in a randomized study in which prophylactic use of carvedilol prevented LVD and reduced mortality in a small population of patients treated with AC.56 The protective effect of nebivolol against AC-induced CMP has been demonstrated in a recent randomized study.57 In 27 patients receiving nebivolol during AC therapy, LVEF and NT-proBNP remained unchanged after 6 months from baseline; conversely, in the placebo group, a significantly lower LVEF and a higher NT-proBNP value were observed. Dexrazoxane, an iron-chelating agent, significantly reduced AC-related cardiotoxicity in adults with different solid tumors and in children with acute lymphoblastic leukemia and Ewing’s sarcoma.15,58,59 Moreover, the same agent was more effective than a prolonged AC infusion in preventing cardiotoxicity in 23 patients with Ewing’s sarcoma treated with doxorubicin.60 Nevertheless, dexrazoxane is not routinely used in clinical practice, and it is recommended by the American Society of Clinical Oncology, as a cardioprotectant, only in patients with metastatic breast cancer who have already received more than 300 mg/m2 of doxorubicin. This recommendation might be explained by the fear of interference with the anti-tumor efficacy of AC and facilitation of the occurrence of secondary malignancies, as well as by its possible myelosuppressive effect. However, meta-analyses found no significant difference, in terms of anti-tumor efficacy or occurrence of secondary malignancies, between patients who were treated with and without dexrazoxane.53,58,61,62 Many other chemical agents have been evaluated, such as co-enzyme Q10, carnitine, N-acetylcysteine, the anti-oxidant vitamins E and C, erythropoietin, the endothelin-1 receptor antagonist bosentan, and the lipid-

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lowering agents probucol and statins; some have shown promising results. Iron-chelating agents, such as deferoxamine and ethylene diamine tetraacetic acid, are also of interest as cardioprotectants (Table 2). However, although preliminary findings found that all these agents may have cardioprotective effects, their utility in preventing CMP needs to be confirmed by further investigation.31,53,58,62,63

The Role of Biomarkers in the Prevention of Cardiotoxicity A pharmacologic preventive approach extended to all cancer patients treated with CMT has a high cost/ benefit ratio and exposes patients to possible adverse effects, including a potential antagonist effect to antitumor activity. The possibility of identifying patients at high risk of developing cardiotoxicity by using cardiac biomarkers provides a rationale for the development of tailored preventive strategies directed at reducing the clinical impact of cardiotoxicity. Two different strategies could be performed: (1) use of specific cardiologic treatments given to cancer patients during the oncologic treatment in the attempt to prevent or blunt the rise of these markers or interfere with their persistence after first increase; or (2) use of cardiologic treatments given only to selected cancer patients identified by an increase in these markers during CMT. A prospective study reported that valsartan, an angiotensin II receptor blocker, given at the same time as doxorubicin was able to prevent an increase in atrial natriuretic peptide, B-type natriuretic peptide, and LV diastolic diameter, as well as prolongation and dispersion in QTc interval, in patients with non-Hodgkin lymphoma.64 Lipshultz et al59 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% v 21%, respectively; P ⬍.001). The possible role of telmisartan in preventing myocardial damage induced by epirubicin was investigated by Cadeddu et al65 in a small randomized study including 49 patients free of cardiovascular diseases and affected by a variety of solid cancers. Twenty-five patients, starting telmisartan 1 week before CMT, 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 interleukin-6, as found in 24 patients receiving only epirubicin. This finding suggests that telmisartan may protect these patients from epirubicin-induced radical species production and antagonize the generation of inflammation, thus preventing the development of early myocardial impairment. The usefulness of TnI screening for a selection of patients requiring prophylactic cardioprotective therapy was investigated in a randomized, controlled trial

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Table 2. Evaluated Cardioprotective Agents

Agent

Class

Mechanism

Carvedilol

␤-Adrenergic antagonist

Nebivolol

␤-Adrenergic antagonist

Valsartan Dexrazoxane

Angiotensin II receptor blocker Chelating agent

Co-enzyme Q10 Carnitine

Dietary supplement Dietary supplement

N-acetylcysteine

Mucolytic agent

Vitamins A, C, and E Erythropoietin Bosentan

Nutrient Hormon Endothelin-1 receptor antagonist

Probucol

Lipid-lowering agent

Fluvastatin Glutathione Selenium

Statin Tripeptide thiol Trace element

Amifostine

Cytoprotective agent

Deferoxamine

Iron-chelating agent

Ethylene diamine tetraacetic acid

Iron-chelating agent

Prevention of free radical formation; prevention of depletion of endogenous anti-oxidants Anti-apoptotic and anti-oxidant properties. Increase of nitric oxide release Inhibition of angiotensin II effects Prevention of free radical formation; binding to iron inhibits DNA topoisomerase Anti-oxidant Anti-oxidant; transfer of longchain fatty acids into mitochondria Promotion of endogenous antioxidant synthesis Anti-oxidant Apoptosis prevention Decrease inflammatory markers (TNF-␣) and the expression of apoptotic signaling proteins Promotion of endogenous antioxidant synthesis Anti-oxidant Anti-oxidant Anti-oxidant; anti-carcinogenic action Anti-oxidant; scavenges reactive oxygen species Production of reactive oxygen species Production of reactive oxygen species

Study Subject Humans

Humans

Humans Humans

Humans Humans

Humans Animal model/humans Animal model Animal model

Animal model Animal model Animal model Animal model Animal model Animal model Animal model

Abbreviation: TNF-␣, tumor necrosis factor-␣.

conducted at our institute.66 The cardioprotective effects of enalapril were evaluated in 473 patients treated with high-dose AC. A total of 114 (24%) patients showed early TnI increase and were randomized to receive enalapril or no treatment. Enalapril was initiated 1 month after the completion of CMT, titrated at the maximal tolerated dose, and continued for 1 year. In the enalapril-treated group, LVEF did not change during the follow-up period. Conversely, in patients not receiving enalapril, a progressive reduction in LVEF and an increase in end-diastolic and end-systolic volumes were observed (Table 3). Moreover, a significantly lower incidence of adverse cardiac events at a

1-year follow-up was found in enalapril-treated patients than in controls (2% v 52%; P ⬍.001).

TREATMENT OF LVD Treatment of AC-induced Cardiotoxicity There is no well-established therapy for AC-induced CMP. Theoretically, this form of CMP should be treated as the other forms of CMP, that is, according to current international cardiologic guidelines. However, guidelines from both European and US cardiology societies do not provide specific recommendations for cancer

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Table 3. Echocardiographic Parameters in Patients Treated With Enalapril (ACE Inhibitor Group) and in

Controls During the 1-Year Follow-up After Chemotherapy Parameter

Baseline

EDV, ml ACE inhibitor group 101.7 ⫾ 27.4 Controls 103.2 ⫾ 20.1 ESV, ml ACE inhibitor group 38.6 ⫾ 10.8 Controls 38.8 ⫾ 10.2 LVEF, % ACE inhibitor group 61.9 ⫾ 2.9 Controls 62.8 ⫾ 3.4

Randomization 100.2 ⫾ 26.1 103.9 ⫾ 21.0

3 Months

6 Months

12 Months

98.1 ⫾ 27.8 97.5 ⫾ 24.5 101.1 ⫾ 26.4 106.4 ⫾ 21.0 107.1 ⫾ 23.9 104.2 ⫾ 25.6

38.7 ⫾ 10.4 40.5 ⫾ 12.2

37.3 ⫾ 10.9 49.8 ⫾ 17.6

37.4 ⫾ 10.3 51.8 ⫾ 16.9

38.5 ⫾ 11.2 54.4 ⫾ 20.1†

61.1 ⫾ 3.2 61.8 ⫾ 4.3

61.9 ⫾ 3.3 54.2 ⫾ 8.1

61.6 ⫾ 3.9 51.9 ⫾ 7.9

62.4 ⫾ 3.5 48.3 ⫾ 9.3†

P* .045 ⬍.001 ⬍.001

Abbreviations: ACE, angiotensin-converting enzyme; EDV, end-diastolic volume; ESV, end-systolic volume; LVEF, left ventricular ejection fraction. Modified from Cardinale et al.66 *P value for repeated measures analysis of variance. †P ⬍.001 versus baseline.

patients who develop HF after cancer treatment.28,29 The response to modern HF therapy of patients with AC-induced CMP has never been fully investigated because, typically, these patients have been excluded from large randomized trials evaluating HF therapies. For this reason, there is a scarcity of data on which to base any recommendation, and whether the use of ACE inhibitor and ␤-blockers can be directly transferred to this particular clinical setting, with similar long-term benefits, remains unclear. Given the lack of clear and well-defined recommendations in monitoring cardiac patients, particularly after the completion of cancer therapy, many authors have suggested only screening programs to look for overt HF; at present, most patients with AC-induced CMP are treated only if symptomatic.67 Conversely, one of the more challenging features of cardiac dysfunction due to AC is that patients remain asymptomatic for a long time.68 In addition, the old and reiterated concept that ACinduced CMP is an irreversible disease, characterized by a poor prognosis, and refractoriness to conventional therapy—with a reported mortality rate up to 50% within 2 years of diagnosis—is currently a subject open to debate.24 This opinion, indeed, was based on findings reported in old studies in which standard HF therapy included only the use of digoxin and diuretics or in studies with small sample sizes.24 –26,54 A few years ago, Tallaj et al69 reported that the cardiac prognosis of AC-induced CMP can be positively affected when patients are treated with ACE inhibitors, and that the addition of a ␤-blocker may further improve their clinical outcome and reverse LVD. Moreover, a recently published prospective study, including the largest population of patients with AC-induced CMP, demonstrated that the time elapsed from the end of CMT to the start of HF therapy (time-to treatment) with ACE

inhibitors and, when tolerated, with ␤-blockers, was a crucial variable for recovery of cardiac dysfunction.27 Indeed, the likelihood of obtaining a complete LVEF recovery is higher in patients in whom the treatment is initiated within 2 months from the end of CMT. After this time limit, however, this percentage progressively decreased, and no complete LVEF recovery was observed after 6 months. After 12 months, the possibility of obtaining at least a partial recovery was completely exhausted (Figure 4). Notably, in this study, the clinical benefit was more evident in asymptomatic patients; indeed, most patients showing a complete recovery from LVD were either asymptomatic or had a low New York Heart Association class at the time HF therapy was initiated. Therefore, monitoring of cardiotoxicity, exclusively based on symptom evaluation, may miss the opportunity to detect early and treat cardiac injury in a still reversible stage. In most previously published studies, the poor response to therapy was possibly due to the underuse of modern drugs, such as ACE inhibitors and ␤-blockers, and to the long (more than 12 months) time to treatment, ie, when cardiac damage was not reversible. This finding emphasizes the crucial importance of the early detection of cardiotoxicity and suggests that an aggressive approach based on the combination of both ACE inhibitors and ␤-blockers always should be considered and attempted in all cases of AC-induced CMP. However, in “real-world” practice, this recommendation is often disregarded in asymptomatic patients and in those recovered from the oncologic disease. This disregard is probably due to the lack of clear, widespread, shared indications from international cardiologic and oncologic guidelines, rather than to economic reasons, considering that in most European countries, the cost of serial monitoring of these patients can be commonly covered by public

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Patients (%)

100 80 60 40 20 0

1–2

2–4

4–6

8–10

6–8

10–12

>12

Months Figure 4. Percentage of patients showing a complete (black bars) or partial (white bars) left ventricular ejection fraction recovery according to the time elapsed from anthracycline administration to start of heart failure therapy. Modified from Cardinale et al.27

health care organizations. In addition, most cancer patients developing cardiac dysfunction do not receive optimal cardiac treatment and are treated only if symptomatic. This is also probably because there is special concern in using ACE inhibitors and ␤-blockers, even if these medications may be highly effective in cancer patients, because these patients are considered frail and the tendency is to not treat them aggressively. Today, however, we have the possibility of preventing cardiotoxicity while we treat the malignancy. The role of TnI in identifying patients at risk of cardiotoxicity and their treatment with ACE inhibitors is emerging as an effective strategy against these complications. When

this kind of approach in not feasible, a complete LVEF recovery and a reduction in cardiac events may be achieved if LVD is detected early after the end of CMT and treatment with ACE inhibitors, possibly in combination with ␤-blockers, is promptly initiated (Figure 5).70

Treatment of Trastuzumab-induced Cardiotoxicity Treatment of trastuzumab-induced cardiotoxicity (TIC) is a more controversial issue. The clinical outcome of patients who develop cardiotoxicity seems more favorable than that of patients with cardiotoxicity in-

Baseline cardiologic evaluation, echo Anthracycline/CMT TnI evaluation at each cycle

TnI POS

TnI not evaluated during CMT Echo at end CMT

TnI NEG

LVD Enalapril for 1 year

No LVD Echo 3 mo No LVD Echo 6 mo

Echo at end of CMT, 3, 6, 9 mo

ACE inhibitor + BB

No LVD Echo 9 mo No LVD

ECHO 12 mo

Echo 12 mo

Echo 12 mo

Clinical follow-up Echo every 6 mo for 5 yr

Echo annually

No LVD

Echo annually

Figure 5. Algorithm for the management of cardiotoxicity in patients receiving anthracyclines. Echo, echocardiogram; CMT, chemotherapy; TnI POS, troponin I–positive; TnI NEG, troponin I–negative; LVD, left ventricular dysfunction; ACE, angiotensinconverting enzyme; BB, ␤-blockers. Modified from Curigliano et al.70

Prevention and treatment of cardiotoxicity of anticancer agents

duced by AC: cardiac function usually improves after withdrawal of the agent and initiation of HF therapy.71 Due to cell loss and a limited capacity of regeneration of cardiac cells, AC-related cardiotoxicity is frequently irreversible. In contrast, most patients with TIC (60%– 80%) significantly improve their LVD when treated with HF drugs. Moreover, in many cases, after therapy with ACE inhibitors and ␤-blockers, re-challenge with trastuzumab does not necessarily lead to re-development of LVD or HF, thus allowing important cancer therapy to be continued without compromising the patient’s cardiac status.72 The concept that TIC is reversible, however, is under discussion.73 Follow-up data from the largest trials show that, in many patients treated with AC followed by trastuzumab, LVD does not recover, that up to two thirds of patients continue to receive cardiac medications after complete LVD recovery, and that many patients display LVEF lower than that at baseline, despite optimal HF therapy.74 Although favorable data on long-term cardiac outcome of patients with TIC are emerging,75 showing that the risk versus benefit of trastuzumab remains in favor of trastuzumab, some uncertainties regarding early diagnosis and management of TIC exist. Despite new, updated guidelines for monitoring patients receiving adjuvant trastuzumab being published periodically, they are specifically focused on the continuation/withdrawal/resumption of trastuzumab therapy.1,74,76 –79 No evidence-based recommendations for the treatment of patients developing LVD, particularly after the completion of trastuzumab therapy, have yet been formulated. Patients with TIC were not treated in a homogenous manner in previous studies, and no prospective randomized trials have ever been performed.74 Also in this setting, management guidelines published by international cardiology societies have not described, as yet, specific medical therapy for the treatment of this different form of CMP. To date, the evidence that supports the use of ACE inhibitors and ␤-blockers in this setting is limited to case series, and it has not yet been demonstrated in clinical trials. As a result, in clinical practice, the decision of whether to treat patients showing asymptomatic decreases in LVEF with these drugs, following American College of Cardiology/American Heart Association/European Society of Cardiology recommendations, may change case by case, and it is mainly based on personal clinical experience of both the cardiologists and the oncologists. Several algorithms have been proposed, but their effectiveness needs to been confirmed in prospective long-term, large trials.1,74,76 –79 Therefore, to date, the true effectiveness of ACE inhibitors and ␤-blockers in improving LVEF and favorably affecting cardiac outcome in patients receiving trastuzumab remains uncertain.

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CONCLUSIONS Cardiovascular safety represents an emerging problem for patients with cancer. Drug regimens used in the treatment of cancer are increasingly complex, with various combinations of agents with differing, and sometimes synergistic, cardiotoxic potential effects. The prevalence of cancer treatment–related cardiovascular disease is increasing, and its management demands a multidisciplinary approach from cardiologists and oncologists, as well as a stronger partnership between cardiovascular and oncology investigators at both the bench and the bedside.

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