Cancer therapy and cardiotoxicity: The need of serial Doppler echocardiography
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Cancer therapy has shown terrific progress leading to important reduction of morbidity and mortality of several kinds of cancer. The therapeutic management of oncologic patients includes combinations of drugs, radiation therapy and surgery. Many of these therapies produce adverse cardiovascular complications which may negatively affect both the quality of life and the prognosis. For several years the most common noninvasive method of monitoring cardiotoxicity has been represented by radionuclide ventriculography while other tests as effort EKG and stress myocardial perfusion imaging may detect ischemic complications, and 24-hour Holter monitoring unmask suspected arrhythmias. Also biomarkers such as troponine I and T and B-type natriuretic peptide may be useful for early detection of cardiotoxicity. Today, the widely used non-invasive method of monitoring cardiotoxicity of cancer therapy is, however, represented by Doppler-echocardiography which allows to identify the main forms of cardiac complications of cancer therapy: left ventricular (systolic and diastolic) dysfunction, valve heart disease, pericarditis and pericardial effusion, carotid artery lesions. Advanced ultrasound tools, as Integrated Backscatter and Tissue Doppler, but also simple ultrasound detection of "lung comet" on the anterior and lateral chest can be helpful for early, subclinical diagnosis of cardiac involvement. Serial Doppler echocardiographic evaluation has to be encouraged in the oncologic patients, before, during and even late after therapy completion. This is crucial when using anthracyclines, which have early but, most importantly, late, cumulative cardiac toxicity. The echocardiographic monitoring appears even indispensable after radiation therapy, whose detrimental effects may appear several years after the end of irradiation.
KeywordsHodgkin Lymphoma Pericardial Effusion Pericarditis Stress Echocardiography Constrictive Pericarditis
In the last decade cancer therapy (CT) has shown a terrific progress leading to an important reduction of morbidity and mortality of several kinds of cancer. The therapeutic management of patients with cancer includes multiple combinations of drugs, radiation therapy and surgery. Many of these therapies produce potential adverse cardiac reactions which can negatively affect the quality of life as well as the prognosis of oncologic patients.
In this view, the early detection of cardiotoxicity due to CT is a critical issue in the clinical setting, in order to interrupt or modulate appropriately CT and even to sustain ventricular performance by cardiac drugs. The traditional screening of patients with cancer includes cardiologic examination, and both EKG and Doppler echocardiography at rest. The monitoring of cardiovascular toxicity might be more accurate by using endomyocardial biopsy  which is, however, invasive and not completely safe. For several years the most common noninvasive method of monitoring cardiotoxicity has been represented by radionuclide ventriculography. Other cardiac tests as effort EKG and stress myocardial perfusion imaging may be used to detect ischemic myocardial complications, while 24-hour Holter monitoring becomes helpful to unmask suspected arrhythmias. Also biomarkers such as troponine I and T [2, 3] and B-type natriuretic peptide (BNP and NT-proBNP) [4, 5] may be useful for early diagnosis of cardiotoxicity.
During time echocardiography is emerged as the choice test for noninvasive evaluation of cardiac disease due to cancer therapy. This tool is essential for the evaluation of left ventricular (LV) systolic and diastolic dysfunction, pericardial disease, myocardial damage and detailed information of valvular heart disease. Nevertherless, Doppler echocardiographic examination is routinely planned only at the beginning of CT in order to document a normal LV systolic function. Further echocardiographic controls during CT are performed only as a consequence of the onset of cardiac symptoms and/or signs, in particular following the administration of recognized cardiotoxic drugs or the radiation therapy. On these grounds, these review attempts to demonstrate the clinical need of serial Doppler echocardiographic evaluation and the potential impact of advanced ultrasound technologies in patients undergoing CT.
Cardiac toxicity of chemotherapic agents and radiation therapy
Cardiovascular toxicity gives its expression in silent (pre-clinical) or overt (clinical) events. Pre-clinical toxicity may be diagnosed by histopathological or biochemical techniques and, even, by detailed imaging techniques. The grading system proposed by the World Health Organization to standardize the report of adverse effects due to CT does not consider laboratory or modern imaging changes  while the more comprehensive system of the National Cancer Institute, including all the important clinical and laboratory changes, should be updated.
Adverse cardiovascular effects of cancer therapy
Adverse cardiac effect
Anthracycline, Mitomycin, Cyclophosphamide, Cisplatin, Trastuzumab, Alemtizumab
Cyclophosphamide, Cytarabine, Imatinib, Thalidomide, Trans-retinoic acid, Busulfan, Radiation therapy
Cisplatin, Vinca Alkaloids, Capecitabine, Interleukin-2 Bevacizumab, 5-Fluotouracil, Radiation therapy
Cisplatin, Bevacizumab, Interferon-α
Etoposide, Talidomide, Paclitaxel, Alemtuzumab, Cetuximab, Rituximab, Transretinoic Acid, Interleukin-2, Interferon-α
Busulfan, Cyclophoshamide, Radiation Therapy
The radiation therapy is applied for CT of lymphoma, breast cancer, thymoma, high and low respiratory ways, esophageal and gastric lesions. Its damage may involve all cardiac structures (pericardium, myocardium, valves, coronary arteries) and peripheral vessels, with variable onset modalities, in relation with dose, irradiation modality, contemporary administration of chemotherapic agents (in particular doxorubicin) and baseline patient's clinical condition . Cardiovascular complications of radiation therapy may be acute and chronic. Some of these are true medical and/or surgery emergencies (cardiac tamponade, acute myocardial infarction, cardiac arrest). Others, mainly due to the progression of coronary atherosclerosis, remain silent for several years and produce during time severe coronary heart disease, even in absence of concomitant cardiovascular risk factors [25, 26]. These vascular lesions correspond to intima hyperplasia and lumen wall collagen deposition, develop throughout a period of about 82 months and involve also carotid arteries, inducing stenosis particularly frequent at the level of bifurcation . Of interest, heart valves are affected by collagen deposition due to radiation therapy and valvular stenosis or regurgitation may be severe, in particular at the level of mitral and aortic valves [25, 27]. Pericardial involvement is, however, the most frequent anatomic consequence of radiation therapy. The right ventricle is more often and more extensively involved. The interval occurring between the radiation therapy and symptom onset is variable, ranging from 2 to 145 months and constrictive pericarditis, silent for several years, produces hemodynamic alterations which become clinically overt even long time after the cessation of x-ray exposition [28, 29]. Importantly, the prevalence of all the abnormalities induced by the radiation therapy increased dramatically over time, making a strong argument for screening because they remained clinically unrecognized. In the past 30 years, radiation therapy has been deeply modified to reduce the total radiation dose administered and to better shield the cardiac structures. The prevalence of these cardiac abnormalities will, thus, realistically decrease in the patients treated more recently.
The main cardiovascular cellular and extracellular targets of CT
Kind of CT
Anthracyclines, Cyclophosphamide, 5-fluorouracil (TNF-α induced apoptosis), Monoclonal antibodies, Radiation therapy
Anthracyclines (atrophy and apoptosis), Cyclophosphamide, Cisplatin, 5-fluorouracil, Monoclonal antibodies (mitochondrial apoptosis), Radiation therapy
Smooth muscle cells
Anthracyclines Cytarabine, Cisplatin, 5-fluorouracil, Cytokines, Arsenic trioxide, Radiation therapy
Anthracyclines, Cisplatin, 5-fluorouracil, Radiation therapy
EKG and cardiotoxicity of CT
EKG represents the traditional support and completion to the clinical examination also for patients undergoing CT but EKG abnormalities are often non specific in this clinical setting. This is particularly true for anthracycline-induced acute toxicity, where non-specific ST-segment and T-wave changes, decreased QRS voltage and QT-interval prolongation have been described. Chronic anthracycline cardiotoxicity (even many years after the completion of therapy) manifests often as life-threatening arrhythmias . 5-Fluorouracil has been demonstrated to be associated with EKG signs of myocardial ischemia while less frequent alterations include arrhythmias . High dose of cyclophosphamide may cause malignant arrhythmias inducing sometimes fatal outcomes . The most severe EKG alterations of interferon-α and interleukin-2 correspond to supra-ventricular and ventricular arrhythmias . Effort EKG test may be useful to unmask coronary artery spasm induced by capecitabine, showing ST-segment elevation accompanied by angina . Twenty-four-hour Holter monitoring and analysis of QT-interval dispersion may be important tools in patients undergoing CT, to detect number and severity of arrhythmias . Increased QT-interval dispersion has been recently found to be a predictor of acute heart failure after therapy by cyclophosphamide  and to persist even in late survivors of childhood anthracycline treatment . In relation with symptoms and signs of congestive heart failure, often developing during CT, it is, however, clear how EKG represents a limited tool for serial cardiologic assessment and early diagnosis of cardiac adverse effects and complications due to CT.
Doppler-echo and cardiovascular toxicity of CT
Today, the widely used non-invasive method of monitoring cardiotoxicity of CT is certainly represented by Doppler echocardiography which allows to identify the main forms of cardiac involvement in cancer patient: LV (systolic and diastolic) dysfunction, valve heart disease, pericarditis and pericardial effusion, and carotid artery lesions.
Also the documentation of valvular heart disease, developing as chronic CT of chemotherapic agents, concerns mainly anthracycline treatment. In a population of 305 patients (median age = 14 years), treated with a cumulative dose ranging 140–450 mg/m2 for childhood malignancy, color flow Doppler detection of mitral regurgitation was evident in 34 patients (11.6%) compared with only 1.8% of a normal population of similar age (p < 0.0001) . Since increased risk of left sided valvular regurgitation, in particular aortic regurgitation, was related to high-dose mediastinal radiation in 129 patients with Hodgkin's disease , echocardiographic screening is highly recommended in this clinical setting. This was confirmed in a retrospective study where, among patients treated with radiation therapy for Hodgkin lymphoma, there was statistically higher than expected rate of valve surgery and coronary revascularization procedures over the next 10 to 20 years  After a mean follow-up of 9.5 years the morbidity of valvular heart disease was about 2.8–2.9% in women who had undergone adjuvant radiotherapy for breast cancer . The echocardiographic analysis of Heidenriech et al  observed that 60% of patients who had experienced irradiation (for Hodgkin's disease) more than 20 years earlier presented mild aortic regurgitation while 15% had moderate to severe aortic regurgitation. Despite the high prevalence of aortic valve disease in these patients, aortic regurgitation was rarely identified by physical examination. The echocardiographic features of radiation-associated valvular disease were described by Hering et al, who reported evidence of combined calcific transformation of the mitral valve, aortic valve and the aortic-mitral aponeurosis, i.e., the junction between the base of the anterior mitral leaflet and the aortic root .
Asymptomatic carotid arterial disease occurs frequently in young patients following head and neck radiation therapy. Doppler-echo scan of carotid arteries allowed to detect increased intima-media thickness in 24% of 42 survivors of Hodgkin lymphoma who had undergone radiation therapy more than 5 years earlier and one patient had greater than 70% stenosis of both common carotid arteries . This findings were recently confirmed in 12/21 patients, irradiated for Hodgkin disease, non Hodgkin lymphoma and seminoma, who developed atherosclerotic carotid vascular disease . In this view, the observation that survivors of childhood Hodgkin disease undergoing mantle irradiation are at increased risk of stroke (RR = 5.62, 95% CI = 2.59 to 12.25, p < 0.0001) is not unexpected .
All together, these findings highlight the ultrasound ability to unmask cardiovascular abnormalities in symptomatic as well as in asymptomatic patients undergoing CT. It emerges also by our retrospective experience including 148 echocardiographic observations from patients referring to our echo-lab for hematologic malignancies and showing CT-related abnormalities of LV function, pericardium and heart valves .
Stress echocardiography and detection of cardiotoxicity
Dobutamine stress echocardiography was tested in several studies to detect subclinical abnormalities of LV function induced by anthracycline cardiotoxicity [77, 78, 79, 80, 81] but the findings of these studies appear insufficient or controversial. In two reports [77, 78] low-dose dobutamine, performed to oncologic patients before, during and after 6 months following chemotherapy, was able to unmask a reduced contractile reserve only in patients who had already depressed LV systolic function and standard Doppler pattern of LV abnormal relaxation at rest. In the experience of Lanzarini et al , young oncologic patients, who had undergone high-dose anthracycline therapy (>400 mg/m2) and had normal LV structure and function at rest, did not show significant modifications during a modified/accelerated dobutamine protocol (achievement of the maximal dose of 15 mg/Kg/min in a short time). On the other hand, Hamada et al, by using high-dose dobutamine (30 mg/Kg/min), evidenced alteration of posterior wall thickness, fractional shortening and transmitral E/A ratio in patients treated by high-dose anthracycline and free of cardiologic symptoms (81).
Stress echocardiography, an optimal tool to unmask coronary artery disease in the general population, remains important also in patients treated by some chemotherapic agents (e.g., capecitabine) and in particular by radiation therapy, which is able to provoke accelerated coronary atherosclerosis. Experiences dealing with the use of stress echocardiography in this clinical setting are, however, lacking until now.
Advanced ultrasound tools for early detection of cardiotoxicity
Some high-tech ultrasound tools as Integrated Backscatter (IBS) and Tissue Doppler have been used with the aim to identify subclinical alterations of both LV structure and function in patients treated by CT.
Analysis of acoustic intensity of the backscattered signal consists of the omni-directional scattering energy redirected back to the transducer, with different intensity according to the density of the reflecting tissue . IBS, which reliably identifies in vivo variations in the regional extent of myocardial fibrosis [83, 84], was successfully used in 28 oncologic patients under HDLV5FU chemotherapy. In these patients the magnitude of both anterior and posterior cardiac IBS values significantly decreased at 48th hour of treatment compared with 0th hour but returned near the baseline values at day 15 (p = 0.003), suggesting a reversible, acute 5-fluorouracile toxicity . In addition, in relation with the recognized diastolic-to-systolic variation of IBS signal , cyclic-variation-IBS of posterior wall appeared decreased in 32 patients with non Hodgkin's lymphoma after 300 mg/m2 of doxorubicin, this decrease being higher in patients treated by moderate and high-dose than in those undergoing low dose .
The 10 commandments for optimal Doppler-echo scan of oncologic patients
Quantify LV geometry (wall thickness, cavity diameters, relative wall thickness, LV mass).
Search regional wall motion abnormalities.
Estimate ejection fraction by 2D apical views if wall motion abnormalities are evident.
Analyze standard Doppler indexes of LV diastolic function.
Record pulsed Tissue Doppler of mitral annulus for detection of increasing LV filling pressure.
Explore structural and functional valve features, in particular mitral and aortic valves.
Visualize pericardium in all ultrasound views (including sub-costal), particularly in patients at high risk (anthracycline, irradiation therapy).
Search ultrasound "comet tail" in patients at risk (anthracycline, irradiation therapy).
Scan carotids in patients treated by head and neck irradiation.
Perform stress echocardiography if coronary artery disease is suspected.
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