Cardiovascular complications of conventional anticancer therapy

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Journal of Cardiovascular Echography 21 (2011) 73–77 www.elsevier.com/locate/jcecho

Review

Cardiovascular complications of conventional anticancer therapy Stefano Oliva *, Agnese Maria Fioretti Cardiology Unit, IRCCS National Cancer Institute ‘‘John Paul II’’ of Bari (Italy) Received 28 April 2011; accepted 6 May 2011; available online 29 June 2011

Abstract Objectives: Even though cancer survival has increased due to both the earlier diagnosis of disease and to the increasingly effective treatments, the side effects of cancer treatments, such as cardiotoxicity, remain clinically important. In fact, the prognosis of cancer patients is worsened by increased cardiovascular mortality and morbidity. This review aims to summarize the main cardiotoxic effects of conventional anticancer therapy, although still widely used and effective, and to verify the most effective treatments and the best preventive strategies. Conclusions: A careful cardiac evaluation before, during and after each chemotherapy treatment is needed to minimize the late cardiotoxic effects of traditional chemotherapy. # 2011 Societa` Italiana di Ecografia Cardiovascolare. Published by Elsevier Srl. All rights reserved. Key words: Cardiotoxicity; Heart failure; Anthracyclines; Cancer therapy; Cardiac prevention.

Riassunto: Complicanze cardiovascolari della chemioterapia convenzionale Obiettivi: Pur essendo aumentata la sopravvivenza dei pazienti affetti da neoplasia, sia per le diagnosi sempre piu` precoci sia per i trattamenti sempre piu` efficaci, gli effetti collaterali cardiologici dei trattamenti antineoplastici rimangono i piu` temuti. Spesso, infatti, la prognosi dei pazienti oncologici peggiora a causa dell’incremento di mortalita` e morbilita` cardiovascolare. Questa rassegna si propone di sintetizzare i principali effetti cardiotossici dei trattamenti chemioterapici ‘‘tradizionali’’, ancora ampiamente utilizzati e di comprovata efficacia clinica, e di verificare i trattamenti piu` adeguati e le migliori strategie preventive. Conclusioni: Un’attenta valutazione cardiologica prima, durante e dopo ogni trattamento chemioterapico e` necessaria per minimizzare gli effetti cardiotossici a distanza dei trattamenti tradizionali. # 2011 Societa` Italiana di Ecografia Cardiovascolare. Pubblicato da Elsevier Srl. Tutti i diritti riservati. Parole chiave: Cardiotossicita`; Scompenso cardiaco; Antracicline; Terapia antineoplastica; Prevenzione cardiovascolare.

1. Introduction Even though cancer survival has increased due to both the earlier diagnosis of disease and to the increasingly effective treatments, the side effects of cancer treatments, such as cardiotoxicity, remain clinically important1. In fact, anticancer therapy, and in particular anthracycline (AN) administration chemotherapy (CHT), is frequently complicated by the development of cardiotoxicity2,3. This subject is of rising concern for both cardiologists and oncologists since many of these side effects are likely to have significant consequences on patient outcomes. Therefore, identifying and understanding these effects is very important

* Corresponding author. E-mail address: [email protected] (S. Oliva).

for the successful management of cancer patients with cardiovascular complications. It must be said that not all CHT drugs are toxic to the heart in the same way. For anticancer therapies in which the incidence of a particular cardiotoxicity was considered rare, these agents were excluded from this review.

2. Chemotherapy-related cardiovascular toxicity The cardiac side effects during conventional CHT administration are many: arrhythmias, high blood pressure, venous thromboembolism, myocardial ischemia and, in particular, left ventricular dysfunction (LVD), from asymptomatic left ventricular ejection fraction reduction up to heart failure (HF). Table 1 lists the conventional CHT mainly related to specific cardiac side effects.

2211-4122/$ – see front matter # 2011 Societa` Italiana di Ecografia Cardiovascolare. Published by Elsevier Srl. All rights reserved. doi:10.1016/j.jcecho.2011.05.005

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of therapy, until 10-30 years from the first dose of treatment4. This significant late effect seems to have several mechanisms but free radical formation is generally accepted as the main mechanism5. Risk factors for AN cardiotoxicity (Table 2) are several and include firstly the cumulative dose of AN. In fact, the prevalence of cardiomyophaty increases significantly when patients are given doses of doxorubicin  550 mg/m2 (7% risk of symptomatic HF)6,7. However, more recent studies have shown that lower cumulative doses can cause similar cardiomyopathy8 and the incidence of clinically significant cardiotoxicity increases progressively post-therapy (26% in patients older than 65 treated with doxorubicin at 550 mg/m2). The administration schedule and the type of AN are similarly related to the ‘‘cardio-oncological’’ risk, because liposomal encapsulated preparations of doxorubicin may reduce cardiotoxicity as demonstrated in phase III clinical trials in metastatic breast cancer when compared with conventional doxorubicin. Mediastinal irradiation (prior or concomitant to AN administration), polichemotherapy or use of new anticancer drugs such as monoclonal antibody-based tyrosine kinase inhibitors trastuzumab9–11, pre-existing conventional cardiac risk factors or comorbidities (diabetes, obesity, renal dysfunction, pulmonary disease, etc.), both young and advanced age and female gender, are other relevant risk factors for developing cardiotoxicity related to AN administration. The risk factors such as young age and the possibility that HF appears very late after AN-based CHT is demonstrated by the Childhood Cancer Survivor study12: thirty years after therapy, 73% of pediatric cancer survivors will develop at least 1 chronic physical health condition and 42% a severe, lifethreatening or disabling condition, or die of a chronic condition. Epirubicin and idarubicin appear to have less incidence of HF13,14 then doxorubicin.

Table 1 Chemotherapy drugs associated to cardiotoxic late effects. Drug

Cardiac side effect

Anthracycline  Doxorubicin  Epirubicin  Idarubicin

AR, LVD AR, LVD AR, LVD

Alkylating agents  Cyclophosphamide  Ifosfamide  Cisplatin

LVD LVD VTE

Antimetabolites  Clofarabine Antimicrotubule agents  Paclitaxel  Docetaxel

MI, AR, LVD MI, AR, LVD

Antimetabolites  Capecitabine  Florouracil

MI, AR MI, AR

Angiogenesis inhibitors  Lenalidomide  Thalidomide

MI, VTE VTE

Legend: AR = Arrhythmias; LVD = Left Ventricular Dysfuntion; VTE = Venous Thromboembolism; MI = Myocardial Ischemia.

2.1. Anthracycline AN, used to treat many hematologic and solid malignances such as Hodgkin’s and non-Hodgkin’s Disease, breast cancer and gastrointestinal cancer, are the most studied of the anticancer drugs with established CHT. The AN cardiotoxicity has been categorized as acute and cronic dysfunction. Acute cardiotoxicity is a rare and transient decline in myocardial contractility manifested immediately after chemotherapy infusion (incidence < 1%) which disappears within one week. However, the chronic progressive cardiotoxicity is defined as ‘‘early onset’’ chronic progressive (within first year after treatment, incidence 1.6-2.1%) and ‘‘late onset’’ chronic progressive. This AN-related heart dysfunction is defined as a particular hypokinetic myocardiopathy, presenting, if not diagnosed and treated early, as dilated cardiomyopathy or HF with or without significant left ventricular reduction, from at least 1 year after completion

2.2. Antimicrotubule agents Over fifteen years ago, some authors have showed that arrhythmias during paclitaxel administration are mainly present as asymptomatic bradycardia (30% of cases). Very few are serious arrhythmias (5%) or myocardial infarction15. But a recent larger database found that only 0.1% of patients suffered from serious cardiac arrhythmias. However, we know that

Table 2 Risk factors for anthracycline cardiotoxicity. Risk factor Cumulative anthracycline dose Rate of administration Type of anthracycline Radiation therapy Other therapy Cardiac risk factors Comorbidities Age Sex

Aspect 2

Cumulative doses  500 mg/m associated with significantly elevated cardiovascular risk Prolonged administration to minimize circulating dose volume may decrease toxicity Liposomal encapsulated preparations may reduce cardiotoxicity Cumulative radiation dose > 30 Gy Trastuzumab and other new drugs (targeted therapy) may increase anthracycline cardiotoxicity Hypertension, diabetes, cardiomyopathy, valvular heart disease, prior cardiotoxic treatment with anthracycline Renal dysfunction, pulmonary disease, endocrinopathies, sepsis Both young and advanced age at treatment are associated with elevated risk Females are at greater risk than males

[(Fig._1)TD$IG]

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Fig. 1. Stage A heart failure patients.

taxanes interfere with the metabolism and excretion of AN and potentiate AN-induced cardiotoxicity, especially at high, cumulative AN doses16. The incidence of HF associated with docetaxel ranges from 2.3% to 8%5 and the increased risk of cardiotoxicity with the addition of paclitaxel to a adjuvant regimen containing AN is not significant.

with lenalidomide. In clinical studies, the incidence of thromboembolism varies, ranging anywhere from 3% to 75%.

2.3. Alkylating agents

3. Management of cardiotoxicity

The clinical manifestations of cardiotoxicity during cyclophosphamide administration range from asymptomatic pericardial effusions to HF and myopericarditis. It is an acute complication (within 1 to 10 days after the first dose administration) and appears to be dose related ( 150 mg/kg and 1.5 g/m2/day)13. Prior AN administration and radiation therapy are considered risk factors for developing this cardiovascular complications.

Therefore, in a recent manuscript20, it is recommended to consider the patients with cancer who are treated with potentially cardiotoxic CHT regimens like a high-risk group for the development of HF. This patients should be treated in accordance with the new American Heart Association giudelines for the treatment of the stage A HF patient21 (Fig. 1). Therefore, in this review we attempt to summarize the current state of knowledge on this most frequent cardiovascular complication of cancer therapy on the basis of a review of the literature.

2.4. Antimetabolites The biggest cardiovascular risk during CHT with antimetabolites is the myocardial ischemia. Angina-like chest pain is more frequent in patients treated with 5-florouracil (5-FU): several prospective studies show that electrocardiogram abnormalities of ST/T waves occur up to 68% of treated patients17–19. High dose administration and continuous infusion have been associated to higher rates of cardiotoxicity. 2.5. Angiogenesis inhibitors Thalidomide and lenalidomide are two effective drugs most commonly associated with the development of venous thromboembolic complications (VTE). If thromboembolic risk of thalidomide is low when administrated alone (< 5%), this risk dramatically increases (3% to 58%) when thalidomide is used in combination with dexamethasone or CHT (particularly, doxorubicin), in the absence of thromboprophylaxis with aspirin or low-molecular-weight heparin (LMWH) respectively in patients at low or high risk of VTE. Lenalidomide, a thalidomide analog with a favorable toxicity profile, shows that the thrombotic risk is still significant

2.6. Other drugs The cardiovascular risk in patients treated with other conventional chemotherapy drugs is negligible.

3.1. Prevention Several approaches have been studied in order to prevent or reduce anticancer-therapy-induced cardiotoxicity, from developing newer molecules, to the use of various cardioprotective agents, of which ICRF-187 (dexrazoxane) showed the most promising results both in adults22,23 and children24. However, the prevention of HF chemotherapy-related, in accordance with AHA/ACC guidelines, must act on ‘‘cardio-oncological’’ and cardiac risk factors: it’s useful to reduce lipid levels and control blood pressure, but especially modify lifestyle. To identify risk factors is necessary for all patients who are undergoing CHT, to obtain baseline assessment of cardiovascular health before initiating therapy. During CHT administration it seems to be not necessary, if risk level is defined as low, to repeat cardiovascular assessment, but the elderly patients, multi-treated, with many cardiovascular risk-factors, or treated with high-dose CHT, need a periodic monitoring of cardiovascular function during treatment. This strategy should be directed at the early detection of myocardial damage for early treatment of CHT.

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3.2. Early detection and treatment Current recommendations suggest that, monitoring during and after cancer treatment exists, but it relate mainly to pediatric populations and do not seem to be based on clear scientific evidence25. When chronic HF is a clinical syndrome caused by CHT, asymptomatic and symptomatic left ventricular dysfunction are managed with b-blockers and angiotensin-converting enzyme inhibitors (ACEi). In a randomized controlled trial (114 pts), the administration of an ACEi such as enalapril, at standard dose in patients who had shown a cardiac troponin I (cTnI) increases soon after highdose CHT and prevents a significant reduction in left ventricular ejection fraction (> 10%). The incidence of this end point was significantly higher in control subjects than in the ACEi group (43% vs 0%; p < 0.001)26. Likewise, in a randomized, single-blind, and placebocontrolled trial, the administration of carvedilol, a b-blocker with significant antioxidant effect (dose: 12.5 mg once-daily) in 25 patients who received at the same time doxorubicin, prevents a significant reduction of left ventricular ejection fraction at six months (68.9% vs 52.3%; p = 0.001)27. These and other manuscripts show that therapy with enalapri and/or carvedilol, currently used in conventional HF therapy, have a central role in the treatment of early cardiotoxicity, because prevent or treat the significant reduction of LVEF by conventional CHT. Furthermore, the experience with AN cardiotoxicity proved that the early detection and treatment of cardiotoxicity could significantly reduce the development of clinical manifestations28. It remains unclear which role the conventional echocardiogram can play in preventing cardiotoxicity29, in particular it is unclear whether the calculation of ejection fraction is the parameter to be used for cardiovascular monitoring because the diagnosis of cardiotoxicity based on symptoms or LVEF reduction is really too late16,30. Currently, cardiotoxicity is defined as LVEF reduction greater than 10 percentage points with final LVEF < 50%, or as LVEF reduction greater than 20 percentage points with final LVEF > 50%. Whether just a reduction of 5 percentage points for the diagnosis of toxicity when there are symptoms such as dyspnea31. In the near future, the new echocardiographic parameters of systolic function (like a strain and strain-rate), seem to have a role in myocardial monitoring during CHT32–34. Nevertheless, conventional parameters of LV systo-diastolic function as the TEI-index seem to be early related to stroke volume in Hodgkin and non-Hodgkin’s Lymphoma treated with AN-based CHT35,36. However, the echocardiography is not the only test able to detection myocardial damage. In fact, cardiac troponins (cTn) are regulatory proteins within the myocardium that are released into the circulation when damage to the myocyte has occurred. Troponins T (cTnT) and I (cTnI) are widely used in the diagnosis of myocardial infarction37.

In the last twenty years there has been an increased the interest in the use of cTn in cancer patients treated with potential cardiotoxic theraphy for preclinical detection of myocardial injury, even when data are lacking on large prospective randomized multicenter trials. The very small increase of cTnI (> 0.04 ng/mL), measured immediately after every cycle of high-dose CHT, in randomized prospective trial is related to significantly (r = –0.87; p < 0.0001) LVEF reduction at follow up38. Furthermore, cTnI value appears to be able to identify the patients at low risk. The persistent low levels of cTnI (< 0.08 ng/mL) soon after CHT (early cTnI) and 1 month later (late cTnI) are related to very low risk level of cardiac events (1%) at the follow up (42 months). Instead, the high levels of early and late cTnI (> 0.08 ng/mL) detect the very high cardiac risk patients (84% of cardiac event at the follow up)39. Moreover, as mentioned earlier, the contemporary early administration of ACEi as enalapril in cTnI positive patients, seems to reduce this risk27. It follows that the predictive positive value (PPV) of cTnI is 85%, and the predictive negative value (PNV) of cTnI is 99% in patients undergoing CHT40. However, the limit of the assay is that troponin has not been demonstrated to be effective in patients at low risk as those treated with adjuvant chemotherapy. Further experiences are needed to define the really extensive use of this assay. The B-type natriuretic peptide (BNP) and the aminoterminal fragment of its precursor (NT-proBNP) represent efficient markers of ventricular dysfunction as they are rapidly produced and secreted by the heart in response to the ventricular wall distention. A recent review has analyzed the results of randomized trials that have investigated the usefulness of measuring the values of BNP in patients with cancer. There are clear limitations of these investigations: small population, different method for detect BNP or NT-proBNP value, different cut-off. In conclusion, determining the value of BNP in patients with cancer does not appear to be as effective as cTnI. 3.3. Follow-up and prevention strategies In practice, there is not a defined approach to the role of the monitoring of cardiac function such as the prevention of cardiotoxicity especially after the end of CHT. Since, it is known that this form of cardiomyopathy may occur even after many months since the end of cancer therapy, it is crucial to continue to check cardiology for a long time, even if it is not yet known what the time limit beyond which we can consider the cancer patients treated with CHT, no more ‘‘at risk’’ of cardiovascular events. A great collaboration between cardiologist and oncologist is needed to achieve this result in order to improve the cardiac health of patients and to determine the best treatment combinations and the best preventive strategies. Conflict of interest The authors have no conflicts of interest to disclose.

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