The clinical value of nuclear medicine in the assessment of irradiation-induced and anthracycline-associated cardiac damage

I. Goethals1,+, O. De Winter1, P. De Bondt1, J. De Sutter2, R. Dierckx1 and C. Van De Wiele1

1 Division of Nuclear Medicine, 2 Department of Cardiology, Ghent University Hospital, Ghent, Belgium

Received 2 May 2002; accepted 18 June 2002

Abstract

Two groups of patients, those treated for Hodgkin’s disease and breast cancer, are particularly at risk of developing late myocardial damage, since radiotherapy (RT) techniques for both patient groups may include (large) parts of the heart, and adjuvant systemic therapy is frequently administered to these patients, in particular anthracycline-containing chemotherapy. Available literature on the monitoring and prediction of RT-induced and anthracycline-associated cardiac damage using nuclear medicine techniques is presented. Based on relevant studies, the risk of overall cardiac disease post-RT and overt congestive heart failure during anthracycline-containing chemotherapy is probably low. Conventional nuclear medicine imaging, i.e. myocardial perfusion scintigraphy, may be of complementary use to echocardiographical evaluation for routine follow-up after RT with modern techniques, in a subgroup of patients with known cardiovascular risk factors. Left ventricle ejection fraction (LVEF) measurements, as assessed by radionuclide angiography for the monitoring of anthracycline-associated cardiac injury, are not very sensitive and early detection will probably be enhanced by combining LVEF measurements with other cardiac function parameters. Also, it may be expected that nuclear medicine techniques using molecular radioligands will constitute an essential future step in the evaluation of subclinical cardiac injury afforded by the combined effect of RT and cardiotoxic chemotherapy.

Key words: anthracycline-associated; cardiac damage; monitoring; nuclear medicine; prediction; radiotherapy-induced

Introduction

Radiotherapy (RT) to the thorax may induce both early and late cardiac adverse effects if parts of the heart have been included in the irradiation field. The early manifestation of cardiac injury is inflammation of peri- and myocardium [1, 2], while late manifestations affect primarily coronary arteries and small myocardial vessels [3, 4]. Clinically, a wide range of manifestations has been described. Pericarditis results from radiation-induced damage to the mesothelial cells lining the peri- and epicardium and usually develops within weeks [5]. Late clinical manifestations, resulting from slowly evolving endothelial cell injury leading to loss of capillaries, ischemia at the microcirculatory level and progressive fibrosis, include valvular dysfunction, conduction defects, coronary artery disease, myocardial infarction and sudden unexpected death several years post-RT [3, 610].

Among chemotherapy-induced toxicity, cardiotoxicity by potent chemotherapeutics such as anthracyclines is of particular concern. Two conditions of cardiotoxicity have been recognized, the first is a dose-independent phenomenon appearing in the immediate period after anthracycline administration and is based on a pericarditis-myocarditis syndrome in patients without previous cardiac disease. The second condition is dose-related and characterized by progressive left ventricle (LV) dysfunction, which may lead to congestive heart failure (CHF) [11]. On pathological examination, progressive anthracycline-related cardiac damage may include restrictive endomyocardial disease, characterized by fibrous thickening of the endomyocardium, and dilated cardiomyopathy, as a result of myocardial fibrosis and hypertrophy of surviving myocytes [12, 13].

The incidence of late irradiation-induced cardiac disease depends on the irradiated volume, total irradiation dose, dose per fraction and on the presence or absence of pre-existing cardiovascular risk factors [5, 1418]. Although overt CHF during doxorubicin therapy may be low [19] (~3% at a dose of 400 mg/m2 and 7% at 500 mg/m2 [20]), the incidence of subclinical left ventricle ejection fraction (LVEF) decline leading to cardiac failure may be substantially higher, up to >50% [12, 2123]. Also, (sub)clinical cardiac damage is known to increase with increasing cumulative dose, additional RT and known cardiovascular risk factors [21, 2427]. Two groups of patients, i.e. those suffering from Hodgkin’s disease and breast cancer, are particularly at risk of developing late myocardial damage, since RT treatment techniques for both patient groups may include (large) parts of the heart, and adjuvant systemic therapy, in particular anthracycline-containing chemotherapy, is frequently administered to these patients.

Irradiation-induced cardiac injury

Hodgkin’s disease
Planar myocardial perfusion imaging (MPI) using 201thallium.
The findings on incidence of late cardiotoxicity, assessed by 201thallium perfusion scintigraphy, and of clinical cardiac events following RT in long-term survivors with Hodgkin’s disease, some of whom have also been treated by chemotherapy, are contradictory (Table 1). Several pilot studies, using planar 201thallium MPI, suggested that mediastinal RT for Hodgkin’s disease produced no significant functional sequelae at long-term follow-up. Morgan et al. [28] found normal 201thallium MPI in 25 asymptomatic Hodgkin’s disease patients 5–16 years after RT. Eleven of these patients were also treated with MOPP (mechlorethamine, vincristine, procarbazine and prednisone)-chemotherapy. Savage et al. [29] obtained similar results, several years after RT, in 12 asymptomatic patients, none of whom were treated with anthracyclines.


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Table 1. Review of late cardiac complications after radiotherapy ± chemotherapy assessed by 201thallium myocardial perfusion imaging
 
Tomographic MPI using 201thallium.
In contrast to the studies mentioned above, of 23 patients treated with RT to the mediastine for Hodgkin’s disease examined by Gustavsson et al. [30], only nine had normal 201thallium MPI. The authors further documented disturbed LV function based on echocardiographical findings. In a study by Maunoury et al. [31], 31 clinically asymptomatic patients, of whom five also received doxorubicin-containing chemotherapy, were evaluated after mantle field RT for Hodgkin’s disease. Based on both visual and quantitative analysis of 201thallium uptake, 21/25 data sets (84%) showed abnormalities. Pierga et al. [32] observed myocardial perfusion defects in 22/26 asymptomatic patients (85%) after RT (and doxorubicin-containing chemotherapy in five patients) for Hodgkin’s disease, using 201thallium single photon emission computed tomography (SPECT). In a recent follow-up study [33], the authors investigated 41 eligible patients and a high rate of myocardial perfusion defects post-RT was confirmed. However, it must be realized that 27/41 patients (66%) had received doxorubicin-containing chemotherapy before RT.

Tomographic MPI using 99mTc-labeled radioligands.
Glanzmann et al. [34] investigated 352 Hodgkin’s disease patients after mediastinal RT with partial inclusion of the heart and applying intermediate total doses between 30 and 45 Gy, with or without chemotherapy (chemotherapy n = 214; doxorubicin-containing chemotherapy n = 94). The authors showed that in a group of 112 patients who underwent heart examination including myocardial perfusion scintigraphy with 99mTc-sestamibi, the result was normal in 93/100 patients (93%) and definitively abnormal in only 4/100 patients (4%); the latter defects corresponding to ischemic lesions. Results were ambiguous, i.e. heterogeneous tracer uptake in 3/100 patients (3%) (Table 2).


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Table 2. Review of late cardiac complications after radiotherapy ± chemotherapy assessed by myocardial perfusion imaging with 99mTc-labeled radioligands
 
MPI and cardiac function imaging with 201thallium and 99mTc-labeled radioligands.
Savage et al. [29] studied myocardial perfusion by planar 201thallium scintigraphy (also see above), and by equilibrium radionuclide angiography (RNA) using 99mTc-pertechnetate, which yielded parameters for LVEF and peak filling rate (PFR), in 12 and 16 irradiated Hodgkin’s disease patients, respectively. Myocardial perfusion was normal in all 12 patients. The authors also documented LVEF and PFR within the normal range, although patients irradiated to large cardiac volumes had lower LVEF and PFR compared with patients who had some part of the heart volume shielded. Constine et al. [35] investigated myocardial perfusion and cardiac function in 50 asymptomatic and youthful patients treated by mantle RT for Hodgkin’s disease with modern RT techniques of whom 17 also received chemotherapy, including doxorubicin in 3/17 patients. The authors documented only mild myocardial ischemia in 2/38 patients (5%) who underwent rest and stress scintigraphies using 201thallium and/or 99mTc-sestamibi SPECT. They also found normal LVEF and PFR in 48/50 and 42/50 patients, respectively, using 99mTc-pertechnetate.

Breast cancer
Tomographic MPI using 201thallium.
Cowen et al. [36] found normal 201thallium MPI in 17 patients after RT (and no adjuvant chemotherapy) for left-side breast cancer, based on planar scintigraphic results.

Tomographic MPI using 99mTc-labeled radioligands.
In a prospective study of 17 left-side breast cancer patients before and after adjuvant RT (and doxorubicin-containing chemotherapy in 3/17 patients) Gyenes et al. [37] showed 50% new fixed left ventricular perfusion defects using 99mTc-sestamibi in 12 patients. The localization of the defects corresponded well with the irradiated volume of the LV. Interestingly, neither ECG (electrocardiographic) changes nor left ventricular segmental wall motion abnormalities could be detected by echocardiography [38]. In a study by Gustavsson et al. [39], perfusion scintigraphy with 99mTc-sestamibi and 99mTc-tetrofosmin showed irreversible defects in only 6/90 patients (7%), all of whom had been treated (with or without adjuvant RT ± cyclophosphamide) for either left- or right-side breast cancer. The observed defects probably related to myocardial fibrosis since, with the exception of one patient, no symptoms of ischemic heart disease were recorded. Left ventricular systolic function was normal in all patients, few signs of diastolic and no valvular dysfunction of clinical significance were observed by echocardiography. In addition, no cardiac deaths among a total of 275 patients included in this study were recorded, despite the fact that in some patients older radiation techniques had been applied. Hojris et al. [40] investigated 17 clinically asymptomatic patients after surgery for left-side breast cancer treated with or without RT plus systemic hormonal treatment in 6/17 patients (35%) or CMF (cyclophosphamide, methotrexate and 5-fluorouracil) chemotherapy in 11/17 (65%) patients. The authors showed that perfusion defects on 99mTc-sestamibi SPECT were equally distributed between the RT and the no-RT treatment group.

Myocardial perfusion and cardiac function imaging with 201thallium and 99mTc-labeled radioligands.
Recently, electrocardiogram-gated myocardial SPECT using 99mTc-labeled ligands enabled the evaluation of cardiac function and perfusion in an integrated method [41]. Using 99mTc-sestamibi gated perfusion SPECT, Hardenbergh et al. [42] performed a preliminary study of cardiac perfusion changes and LVEF in 10 patients with breast cancer treated with RT and doxorubicin-based chemotherapy. The authors indicated that cardiac function, as assessed by LVEF, was not altered by the combined treatment of RT and chemotherapy, except in one patient with known cardiovascular risk factors. On the other hand, new perfusion defects were observed among 7/7 patients treated with doxorubicin and RT, if portions of the LV received >50% of the RT dose. In this study, the perfusion defects did not seem to correlate with clinical events, but follow-up was short and thus clinical significance is unclear at the present time.

Other SPECT tracers for imaging irradiation-induced cardiac injury
Other SPECT tracers such as 111In-antimyosin and 123I-meta-iodobenzylguanidine (123I-MIBG) have occasionally been explored. Since 111In-antimyosin antibody binds to intracellular myosin only when the sarcolemma has been disrupted, 111In-antimyosin uptake may correlate with disrupted integrity of myocytes [43]. However, irradiation-induced cardiac damage is believed to be caused by endothelial cell injury and generally myocyte integrity is believed to be left intact by RT. Ricart et al. [44] demonstrated increased myocardial uptake of 111In-antimyosin, by means of 48-h heart-to-lung ratios, in patients who had recently been treated by both low- and high-dose RT. The authors argued that subclinical damage to the heart might occur at doses previously assumed to be without risk of adverse cardiac effects.

123I-MIBG is a guanidine analog that, unlike noradrenaline, is not metabolised by monoamine oxidase or catechol-o-methyl transferase. Since initial uptake of the tracer reflects myocardial neuron integrity and adrenergic release function, 123I-MIBG is considered to be suitable for the study of myocardial adrenergic innervation [45]. Valdés Olmos et al. [46] demonstrated the feasibility of 123I-MIBG imaging after RT. Progressive loss of cardiac function after RT may not exclusively be imputed to endothelial cell injury; alterations in sympathetic innervation of the heart may also be involved. During the late phase after RT, the authors demonstrated that, in comparison with normal subjects, cardiac uptake at 4 h post-injection and myocardial wash-out rate of 123I-MIBG was significantly decreased in 18 cancer therapy patients.

Anthracycline-associated cardiotoxicity

Imaging of cardiac function using radionuclide angiography
Initial guidelines that allowed grading of CHF as mild, moderate or severe, on the basis of a progressive fall in LVEF using serial RNA, were defined by Alexander et al. [47]. Implementation of these guidelines in the monitoring of cardiac function at rest in adults during anthracycline-containing chemotherapy is now well established [48]. In the study that proposed the guidelines, it was indicated that the total cumulative doses of doxorubicin that precipitated CHF and those that did not varied widely, thus indicating that there may be a considerable individual variability in the tolerance to anthracyclines [48]. Interestingly, a four-fold reduction in the incidence of overt cardiac failure in those patients whose management was concordant with proposed guideline criteria was documented.

To date, various scintigraphic strategies, e.g. multiple gated acquisition, have been used for the early detection of anthracycline-associated cardiac damage, and the focus has been on changes in LVEF and other systolic function parameters, e.g. wall motion abnormalities [4951]. In a study including 55 pediatric patients treated with doxorubicin, the authors documented a high incidence of decreased LVEF and abnormal myocardial movements, even at low cumulative doses of 180–200 mg/m2 [52]. Anthracyclines may also negatively influence cardiac diastolic function [53, 54], and since changes in LV diastolic function can occur before LVEF falls to subnormal levels, some have argued that diastolic as well as systolic function should be examined for the early detection of anthracycline cardiotoxicity [5557]. Interestingly, at long-term follow-up after chemotherapy, diastolic function was normal in 2/4 patients (50%) with a history of severe CHF manifested 2–116 months earlier who were asymptomatic at the time of the study and had normalized LVEF values. The authors further indicated that other techniques with specific myocardial tracers may be more appropriate to detect persistent anthracycline-induced cardiac damage at the long-term follow-up after anthracycline-containing chemotherapy (see also below) [58].

Monitoring of anthracycline-associated cardiotoxicity by 111In-antimyosin SPECT
111In-antimyosin traces myosin in the myocytes. Using 111In-antimyosin SPECT, myocardial uptake of the tracer was documented in 17/20 patients (85%) with advanced breast carcinoma treated with doxorubicin at a total cumulative dose of 500 mg/m2 [59]. Moreover, 8/20 patients (40%) with decreased LVEF presented with more intense 111In-antimyosin uptake in comparison with those with normal LVEF. The same authors performed 111In-antimyosin antibody scans and LVEF measurements in 32 patients with breast cancer and in nine patients with other tumours, all of whom received chemotherapy including anthracyclines [60]. 111In-antimyosin uptake in the myocardium, quantified by means of a heart-to-lung ratio, was observed in 38/41 patients (92%) after chemotherapy and a correlation between the degree of 111In-antimyosin uptake and the cumulative dose of anthracycline was shown. Patients with a decreased LVEF showed more intense 111In-antimyosin uptake, indicating more severe myocardial damage. In another study of 30 patients with sarcomas who were treated with doxorubicin, increased 111In-antimyosin uptake identified patients at risk of CHF before deterioration of LVEF [61]. Five out of seven patients (71%) presented with a decrease of >=10% in LVEF and developed symptomatic heart failure at a total cumulative dose of 420–600 mg/m2. These patients were characterized by increased 111In-antimyosin uptake even at an intermediate dose of 240–300 mg/m2. The same authors confirmed, in a larger study of 36 cancer patients treated with chemotherapy including doxorubicin, that patients with more intense 111In-antimyosin uptake at intermediate doses tended to be those with more severe functional impairment at maximal cumulative dose [62]. In the study by Nousiainen et al. [58], increased 111In-antimyosin uptake was present in four patients with severe CHF manifested several months earlier after anthracycline therapy, although two patients had full clinical recovery at the time of scanning.

Monitoring of anthracycline-associated cardiotoxicity by 123I-meta-iodobenzylguanidine SPECT
123I-MIBG is useful for the investigation of the myocardial adrenergic neurotransmitter system [63]. Decreased myocardial retention of 123I-MIBG has been reported in patients with anthracycline-induced cardiomyopathy, and the wash-out rate seems to correlate with cumulative dose [64, 65]. Moreover, the degree of reduction of myocardial 123I-MIBG retention may correlate with the severity of the fall in LVEF and reduced retention of 123I-MIBG may precede a decrease in LVEF [6668]. Nousiainen et al. [58] showed that reduced 123I-MIBG retention may be present not only at the time of anthracycline therapy, but also several years after the last anthracycline dose in patients who clinically recovered from heart failure.

Other SPECT tracers for the imaging of anthracycline-associated cardiac injury
131I-fatty acids, 123I-paraphenyl pentadecanoid acid (131I-pIPPA), have been used in a rat model to document the myocardial metabolism in conditions of doxorubicin therapy. An impairment of myocardial utilization of the tracer, possibly mediated by a carnitine deficiency, was observed [69]. In the study by Nousiainen et al. [58], one patient with decreased LVEF at the time of scanning showed myocardial fatty acid hypometabolism, whereas three other patients showed homogeneous fatty acid uptake, one of whom had a decreased LVEF and two with normal LVEF.

Discussion

With increasing survival rates of cancer patients treated by modern RT techniques, concern about long-term side-effects of RT has risen, more so since adjuvant chemotherapy, which often includes cardiotoxic drugs, is increasingly used. Also, it has been shown that the combination of both treatment modalities increases the risk of developing cardiac damage [26, 27]. The high rate of cardiovascular mortality after RT in pilot studies [15, 18, 30] may be related to out-dated treatment regimes, which are no longer used. Older RT techniques employed higher radiation doses and lacked appropriate cardiac shielding [35]. These RT treatment features have undoubtedly influenced the development of cardiac damage and it is now recommended that orthovoltage RT and high fraction doses should be avoided to minimize late tissue damage to the heart [70]. Additionally, the use of tangential fields, which seem to spare the heart from harmful irradiation, is recommended, whenever this option is available [36].

Scintigraphic studies performed with 201thallium showed that ~70% of patients treated with RT ± chemotherapy had myocardial perfusion defects [30, 33]. In contrast, scintigraphic studies using 99mTc-labeled radioligands indicated an incidence of ~5% for myocardial perfusion defects [34]. Probably, false-positive defects and temporary reversible abnormalities detected after sustained exercise may have accounted for the high incidence of myocardial perfusion defects visualized with 201thallium scintigraphy in comparison with 99mTc-labeled radioligands. On the other hand, the use of planar scintigraphy, suffering from low sensitivity when compared with tomographic scintigraphic acquisition, may have resulted in false-negative results in 201thallium studies [28, 29, 36]. Recent SPECT studies with 99mTc-labeled radioligands, using strict inclusion criteria, seem to confirm a low rate of late perfusion deficits following external RT ± chemotherapy, and an increased risk for ischemic cardiac disease may only be observed in patients with known cardiovascular risk factors [34, 39, 40, 42]. Finally, the fact that several authors included too few patients to discover rare adverse effects, as is the case for late cardiac injuries, may have reduced the statistical power of these studies, and observed differences between patients treated with and without RT could simply arise by chance [40, 42].

In addition to MPI in patients treated with anthracycline-containing chemotherapy, other scintigraphic parameters for both systolic and diastolic cardiac function have been recommended to assess cardiac injury. Of these parameters, LVEF measurement at resting conditions is the most frequently used and may offer a flexible strategy that permits discontinuation of anthracycline administration as soon as significant LVEF decline is detected [48]. However, it has been pointed out that abnormal LVEF values may not be adequately predictive of early and late cardiac outcome in clinically asymptomatic patients treated with anthracycline-containing chemotherapy [71]. Deterioration of cardiac function may temporarily be masked by reserve capacity and compensatory mechanisms. Therefore, RNA may not be suited for the early detection of anthracycline-induced cardiotoxicity. However, the number of studies supporting an additional benefit for the detection of chemotherapy-induced cardiac damage with specific myocardial tracers (such as 111In-antimyosin and 123I-MIBG) is limited to date, these techniques appear to be more sensitive than LVEF measurements. Increased 111In-antimyosin uptake, reflecting widespread and persistent myocyte damage, and decreased myocardial 123I-MIBG uptake, indicating permanent cardiac adrenergic denervation, have been shown at long-term follow-up after the manifestation of heart failure [58, 66]. Presumably, 111In-antimyosin and 123I-MIBG SPECT may identify patients at risk of late cardiac sequelae and episodes of CHF after treatment with anthracyclines ± RT. However, whether abnormalities in 111In-antimyosin and 123I-MIBG uptake have prognostic value in these patients remains unclear.

Conclusion

The risk of any form of cardiac disease post-RT and overt CHF during anthracycline-containing chemotherapy is probably low [5, 35, 42, 72]. However, every effort must be made to reduce the volume of myocardium irradiated and the dose to the cardiac tissue and coronary arteries to minimize the risk of radiation-associated adverse events. Doxorubicin-based chemotherapy increases the frequency and severity of (sub)clinical cardiac damage, in a dose-dependent manner [27]. Therefore, in patients treated with both RT and chemotherapy, cumulative doses should be carefully monitored.

Assessing cardiac damage by conventional nuclear medicine imaging, i.e. myocardial perfusion scintigraphy, may be of complementary use to echocardiographical evaluation for routine follow-up after RT with modern techniques, in a subgroup of patients with known cardiovascular risk factors.

For the monitoring of anthracycline-induced cardiac injury, LVEF measurements, as assessed by RNA, are not very sensitive and early detection will probably be enhanced by combining LVEF measurements with other cardiac function parameters. Further research is needed to establish the clinical value of molecular radioligands, but it may be expected that these nuclear medicine techniques will constitute an essential step in the evaluation of subclinical cardiac injury resulting from the combined effect of RT and cardiotoxic chemotherapy.

Footnotes

+ Correspondence to: Dr I. Goethals, Division of Nuclear Medicine, Polikliniek 7, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Tel: +32-9240-30-28; Fax: +32-9240-38-07; E-mail: ingeborg.goethals{at}rug.ac.be Back

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