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Long-Term Prospective Follow-Up Study of Cardiac Function After Cardiotoxic Therapy for Malignancy in Children

Tuija Poutanen, Tero Tikanoja, Pekka Riikonen, Annuli Silvast, Mikko Perkkiö

From the Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland, Medix Clinical Laboratories, Kauniainen, Finland.

Address reprint requests to Tuija Poutanen, MD, Lintuviidankatu 22, FIN 33340, Tampere, Finland; email: tuija.poutanen{at}koti.tpo.fi.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: To evaluate cardiac function by means of conventional and three-dimensional echocardiography (3DE) and measurement of natriuretic peptides in children and adolescents previously treated for childhood malignancy using individual follow-up data and matched control children as reference criteria.

Patients and Methods: Thirty-nine survivors of childhood malignancy were examined in 1994 and 1998. The mean time from the diagnosis was 8.6 (3.9 to 16.8) years and between cardiac evaluations was 4.1 (3.3 to 5.1) years. Patients were divided into two groups according to therapies given (group I (n = 30): no cardiac irradiation, median cumulative anthracycline dose 210 mg/m²; group II (n = 9): irradiation in the cardiac region, median cumulative anthracycline dose 180 mg/m²).

Results: Fractional shortening (FS) in 1994 was higher than in 1998 (32.5 ± 4.3 vs. 30.3% ± 3.3%, P = .009). 33% of patients in group I and 56% in group II in 1994 and 30% of patients in group I and 67% in group II in 1998 had N-terminal of the propeptide-atrial natriuretic peptide (NT-proANP) levels exceeding the 90th percentile of controls. In 1998, both groups (I and II) had lower ejection fraction (EF) measured by 3DE than their matched controls (52.9 ± 5.2 vs. 58.8% ± 3.1%, P < .001 and 50.0 ± 6.6 vs. 60.8% ± 3.2%, P = .024, respectively). Left atrial maximum volumes/body surface area were smaller in the patients than in controls. B-Type natriuretic peptide values did not differ significantly in either group.

Conclusion: Left ventricular contractility decreases slowly even years after cardiotoxic cancer therapy in children. 3DE and NT-proANP measurements are effective methods to evaluate the cardiac function in these patients.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
CARDIAC COMPLICATIONS of chemotherapy and irradiation are a notable risk for the increasing number of children and adolescents surviving childhood malignancies. Anthracycline-induced cardiotoxity is a well-known problem, which may ultimately lead to congestive heart failure. The severity of myocardial damage is proportional to the cumulative dose received^1–4 but there is a range of cumulative anthracycline doses that will produce clinical cardiomyopathy.^5,6 Radiation therapy seems to have an additive effect on anthracycline cardiotoxicity.^7–10 Cardiomyopathy is a serious problem among young patients treated with anthracyclines, reinforcing the need for strategies for early detection of patients at risk of anthracycline-induced clinical heart failure.⁴ The means of cardiac follow-up now available are unsatisfactory for early detection of risk patients.

Three-dimensional echocardiography is a new noninvasive imaging technique that has been shown to be accurate in determining cardiac volume and mass.¹¹ Our recent study has shown the suitability of three-dimensional echocardiography (3DE) for assessing phasic left atrial and left ventricular volumes in children.^12,13 Time-volume data obtained by radionuclide angiography have been used to evaluate left ventricular systolic and diastolic function in patients with anticancer therapy. Systolic and diastolic filling parameters were found to be abnormal by radionuclide angiography during short-term anthracycline chemotherapy.¹⁴ The value of 3DE assessment of the volumes, mass, and diastolic filling indexes in cardiac evaluation after cancer therapy is not known.

Natriuretic peptides are hormones that are produced within the heart and are released into the circulation in response to stretch of the cardiac chambers. Circulating levels of atrial natriuretic peptide (ANP), the N-terminal part of the propeptide (NT-proANP), and the predominantly ventricular-derived B-type natriuretic peptide (BNP) are increased in patients with left ventricular dysfunction.^15–17 Our previous study showed increased NT-proANP levels in patients who had received treatments for childhood cancer.⁹

The purpose of this study was to evaluate cardiac function by means of conventional and three-dimensional echocardiography and natriuretic peptides in children and adolescents previously treated for childhood malignancy using individual follow-up data and matched control children as reference criteria.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The study was carried out in Kuopio University Hospital from February 1998 to February 1999. Written informed consent for the study was obtained from the parents or subjects. The study was approved by the research ethics committee of the hospital.

Patients
Altogether, 39 children or adolescents who had received anthracycline-containing chemotherapy and/or cardiac irradiation for treatment of cancer participated in the study. All of them had follow-up data from our previous study in 1994.⁹ The time from diagnosis at the time of study (1998) was 3.9 to 16.8 (mean 8.6) years. The mean time between cardiac evaluations was 4.1 year. In 10 patients (eight of 30 in group I and two of nine in group II), the time from diagnosis was longer than 10 years. The mean age of children was 10.0 (1.8 to 16.7) years at the time of evaluation in 1994, and the mean age was 14.1 (6.1 to 20.7) years at the time of evaluation in 1998. Patient characteristics are listed in Table 1. Five patients (12%) had had a relapse of their malignancy. Twenty-nine (74%) had been treated for leukemia and 10 (26%) for solid tumors (Hodgkin’s disease, n = 4; Wilms’ tumor, n = 4; rhabdomyosarcoma, n = 1; non-Hodgkin’s lymphoma, n = 1). Twenty had received radiotherapy (extra thoracic, n = 11; total-body irradiation (TBI) or thoracic irradiation, n = 9); bone marrow transplantation (BMT) had been performed in seven subjects. Patients were divided into two groups according to the treatments given. Group I consisted of 30 patients with cardiotoxic cancer treatment without cardiac irradiation. Group II consisted of nine patients with cardiac irradiation: one with autologous BMT and with thoracic irradiation 24 Gy, four with allogenic BMT (three with TBI 12 Gy and one with TBI 10 Gy and spinal irradiation 12 Gy), and four with thoracic irradiation (12, 20, 30, and 41 Gy). In our hospital, anthracyclines have been given by 1- to 24-hour infusions from 1991. Of the patients studied, 23 (59%) had received anthracyclines as bolus injections and 16 (41%) as infusions. Two patients in both groups had a slightly reduced exercise tolerance (class II according to the functional classification of the New York Heart Association). In addition, two patients of group I were classified as NYHA III (one with portal hypertension and one with Down’ s syndrome and grave obesity). One patient had cardiac medication (enalapril), and cardiac function tests in 1994 and 1998 were performed on this patient during medication.

Laboratory Measurements
NT-proANP concentrations were measured as described earlier.⁹ The detection limit of the method was 0.10 nmol/L. Plasma BNP concentrations were determined with an immunoradiometric assay kit (SHIONORIA BNP) using two monoclonal antibodies.¹⁸ The interassay correlations of variance at levels of 18.2 and 290 ng/L were 11.0% and 7.0%, respectively. The detection limit of the BNP method was 4 ng/L.

Echocardiographic Examination
Transthoracic echocardiographic examination was performed with the patient lying supine or in the left lateral semirecumbent position. Sedation was not used. Examinations were performed by a single observer (TP) using a GE Vingmed System FiVe ultrasound scanner (GE Medical Systems, Horten, Norway) and saved in digital form on the hard disk of the ultrasound scanner. The transducer frequencies used were 2.2 MHz octave, 3.5 MHz, and 5 MHz. Standard parasternal, apical, and subcostal views were used. 3DE was performed by using rotational image acquisition from an apical view for the left ventricle and from a parasternal long axis view for the left atrium, with ECG gating and without respiratory gating. The features of our three-dimensional echocardiographic method have been described previously.^12,13

Echocardiographic Analysis
The echocardiographic data were analyzed by a single observer (TP). Previous studies showed good intra- and interobserver repeatability of the measurements.^12,13

M-mode. All measurements in the M-mode were made according to the recommendations of the American Society of Echocardiography.¹⁹

2DE. Left ventricular (LV) end systolic and end diastolic volumes were determined (single plane area-length method) and LV mass (LVM) was calculated (area-length-method) according to American Society of Echocardiography recommendations.²⁰

Doppler echocardiography. Transmitral flow velocity patterns were recorded from the apical four chamber view, with small sample volume being positioned between the tips of the mitral valve leaflets. The angle between the sampling beam and the mitral inflow was less than 20 degrees. Measurements obtained on three consecutive heart cycles were averaged.

3DE. The three-dimensional data sets were analyzed with a detached computer. LV ejection fraction (EF) was calculated from end diastolic volume (EDV) and end systolic volume (ESV). LVM was calculated as the difference between epicardial and endocardial end diastolic volumes multiplied by the specific gravity of myocardium (1.05 g/mL). Peak ventricular ejection rate (PER) and peak filling rate (PFR) represent the greatest volume change per time during three frame intervals in 3DE recording (on average 40 ms) in the ejection phase and in the filling phase of the time-volume curve. The rate of the volume change was normalized by left ventricular stroke volume (SV, ml). Time to peak filling rate was measured from end systole to the time of peak left ventricular filling rate. Left atrial (LA) cyclic volume change was calculated as the difference between LA maximum (LAmax) and LA minimum volumes (LAmin). Left atrial stroke volume (LASV) is the volume reduction from the onset of atrial systole to the minimum volume at the end of diastole. The last 15% of the heart cycle was chosen to represent this time period of diastole. The passive emptying of LA volume was defined as the LA maximal volume minus the LA volume at the onset of atrial systole. The relation of atrial stroke volume to cyclic volume change was calculated.

Mean time-volume curves of LA and LV were calculated to obtain a visually informative way of representing the volume changes in the patient and control groups, as described previously.^12,13 For each patient we first calculated the time intervals from R-wave to maximum/minimum volume and from maximum/minimum volume to the end of heart cycle. Both time intervals were divided into 20 equal parts (5%). The respective volumes were interpolated at each time point. Data on the subjects in each group were then averaged to gain a sum curve, which represents the times from R-peak in ECG (by 5% intervals before and after the maximum volume point) and the respective volumes.

Statistical Analysis
The data are given as mean (SD) and, when considered informative, as median and 90th percentile. Group means were compared between children with cardiotoxic treatment and matched control children with Student’s paired t test. The nonparametric Wilcoxon or Mann-Whitney tests were used. P values were multiplied by the number of groups in the same analysis. Pearson’s correlation coefficient was used, and in cases of non-normality, Kendall’s correlation coefficient was used. Multivariate analysis was performed by logistic regression using decreased FS as a dependent variable. Receiver operating characteristic (ROC) curves were constructed to assess sensitivity and specificity of EF (2DE) and EF (3DE) as an indicator of increased NT-proANP level of decreased FS. The area under the curve was calculated for both EF estimates.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The results from the year 1994 are presented only in the section of prospective follow-up. All the other results are from the year 1998.

Natriuretic Peptides in 1998
The results of NT-proANP analysis are shown in Figure 1. NT-proANP levels decreased with increasing age in reference children (r between NT-proANP and age = -0.36, P = .003). In patients, NT-proANP levels increased with increasing age (r = 0.36, P = .027). NT-proANP levels did not correlate with the time from diagnosis or the cumulative anthracycline dose. NT-proANP median and 90th percentile values (nmol/L) were 0.13 and 0.39 in group I, 0.27 and 0.59 in group II, and 0.10 and 0.19 in the control group, respectively. The values of group I and group II differed significantly from the values of control children (P = .030 and .003, respectively). The difference between groups I and II was insignificant (P = .100). Fifteen of 39 (38%) of patients had NT-proANP concentrations equal or above the 90th percentile (0.19 nmol/L) of the controls (group I nine of 30 and group II six of nine). There was no significant difference in NT-proANP values between patients with time from diagnosis less than or more than 10 years (median [range], 0.13 [0.10 to 0.59] vs. 0.27 [0.10 to 0.65], P = .070).

View larger version (18K): [in this window] [in a new window]   Fig 1. NT-proANP values of control children and patients in 1994 and 1998. The solid lines represent the median values and the dashed lines the 90th percentile values of NT-proANP in each group. Patient groups 1 and 2 are marked with open and solid dots, respectively. The individual NT-proANP values in 1994 and 1998 are paired with a line. * Data adapted9.

BNP values did not correlate with age, the time from diagnosis, the cumulative anthracycline dose, or NT-proANP in either group. BNP median and 90th percentile values (ng/L) were 10.0 and 22.7 in group I, 8.0 and 38.9 in group II and 5.9 and 21.4 in the control group, respectively. The values of group I and group II did not differ significantly from the values of control children (P = .066 and .455, respectively). Four of 39 (10%) patients (three of 30 in group I and one of nine in group II) exceeded the 90th percentile BNP concentration (21.4 ng/L) of the controls. BNP values were higher in patients who had received anthracyclines as rapid infusion compared with those with slow administration (10.2 and 42.4 vs. 5.7 and 14.8 ng/L, P = .018). No difference was found in NT-proANP and BNP values between children treated with anthracyclines before or after 4 years age (P = .817 and .354, respectively)

A positive correlation was found between BNP and LAMIN/BSA (r = 0.71, P = .013) in group II. BNP correlated with LVSV/BSA (3DE) in both groups (r = 0.76, P < .001 in group I and r = 0.57, P = .048 in group II) and with EDV/BSA (3DE) in group II (r = 0.71, P = .013).

Echocardiography in 1998
Table 2 summarizes the Doppler echocardiographic results. The patients in group II had significantly higher heart rate than their matched controls. In group II, A wave was higher and EAT was shorter than in the controls. No correlation was found between heart rate and A, but EAT correlated inversely with heart rate in group II (r = -0.78, P < .001). No signs of diastolic dysfunction were found in group I.

View larger version (19K): [in this window] [in a new window]   Fig 2. Averaged left atrial and left ventricular time-volume curves during the heart cycle in patient groups I (A, B) and II (C, D). The darker lines represent the patients, and the lighter lines represent the matched control children.

View larger version (14K): [in this window] [in a new window]   Fig 3. Receiver operating characteristic curves (ROC curves) for EFs assessed by 3DE and 2DE. The sensitivities and specificities were calculated using NT-proANP above 0.19 nmol/L (90th percentile of the healthy controls in 1998) and/or FS below 28% (-2SD value of 169 healthy children; T. Poutanen, unpublished) as abnormal findings.

None of the risk factors was significant in a multivariate model including total anthracycline dose, cardiac irradiation, sex, and age less than 4 years at the time of treatment.

Results of the Prospective Follow-Up (From Years 1994 and 1998)
NT-proANP results in 1994 and in 1998 are illustrated in Figure 1. The control children in 1994 (ages 1.3 to 15.8, median 6.9 years) were slightly younger than control children in 1998 (ages 1.4 to 17.2, median 9.9 years) (P = .045). The 52 control children in 1994 had higher NT-proANP levels than the 67 control children in 1998 ([median, 90th percentile], 0.15, 0.26 vs. 0.10, 0.19, P = .003), although the selection criteria and methods of sampling and analysis were closely similar. Thirty-three percent of patients in group I and 56% in group II in 1994, and 38% of patients in group I and 67% in group II in 1998, had NT-proANP levels exceeding the 90th percentile of controls. Results of fractional shortening are presented in Figure 4. FS had decreased in 69% and increased in 31% of the patients. FS below 28% (mean-2SD in 169 control children in our laboratory) was found in seven patients in 1994 and in eight patients (seven females, one male) in 1998.

View larger version (24K): [in this window] [in a new window]   Fig 4. Fractional shortening (FS) values of patients in 1994 and 1998. Patient groups I and II are marked with open and solid dots, respectively. * Data adapted9.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Anthracycline therapy and chest irradiation may lead to continuing loss of myocytes, resulting in a progressive decrease in left ventricular mass. Earlier follow-up studies after cardiotoxic therapies for cancer have shown reduced left ventricular mass²² and thinning of the left ventricular posterior wall and interventricular septum.^2,7,8,23 The risk of cardiac complications has been reported to correlate with the cumulative dose of anthracyclines and with cardiac irradiation.^2,7,8,10 The results of our study are in accordance with these studies.

Intravenous infusion instead of bolus injection of anthracyclines seems to reduce their cardiotoxic effects.²⁴ However, long-term follow-up is needed to determine whether the reduction in cardiotoxicity is permanent or short-lived.²⁵ In our study, BNP was slightly higher in patients who received anthracyclines as a bolus injection, but no other correlations with the method of anthracycline administration and the parameters reflecting cardiac dysfunction were found. Thus, slow administration of anthracyclines may have at most a modest cardioprotective effect in the long term.

The results of this study are consistent with our previous study showing elevated NT-proANP values in patients after cardiotoxic therapy, especially in those with thoracic irradiation.⁹ In healthy children, NT-proANP values decreased with increasing age, whereas in patients, increasing values with increasing age were found. Although mean NT-proANP levels were lower in 1998, the number of patients exceeding the 90th percentile values of contemporary control children was the same in both the 1994 and 1998 studies. The slightly lower NT-proANP levels in 1998 seen in both control children and patients may be due to older age or to slight changes in the material used in NT-proANP analysis in the years 1994 and 1998. Despite decreased LV contractility, our patients were in good clinical condition and none of them had low FS values. Increased NT-proANP values in these patients are suggestive of LV diastolic dysfunction. Patients with clearly rising NT-proANP values were seen in both patient groups. These patients should be observed as risk patients, and the introduction of therapy with angiotensin-converting enzyme inhibitors is to be considered.

The concentration of BNP is increased in patients with cardiac disease, particularly in those with heart failure.¹⁷ Increasing BNP concentrations have been associated with decreased ejection fraction.^15,26 The diagnostic usefulness of BNP determination for the diagnosis of heart failure has been demonstrated.^27,28 A previous study in cancer patients showed increased levels of BNP, NT-proANP and ANP, and a correlation with the impairment of left ventricular function during anthracycline therapy.²⁹ In our study, BNP values were not significantly increased in either group. The proportion of patients having BNP values in excess of the 90th percentile of reference children was 10%, as statistically was to be expected. Thus, BNP was not clinically useful in our material.

We used the digitized transthoracic 3DE method to assess LV and LA function. LV volumes and the filling and emptying indices for LV calculated from the 3DE time-volume data showed minor abnormalities in patients. 3DE was a more sensitive method to detect decreased LV contractility than FS by M-mode or EF by 2DE. LA volumes and their changes during the heart cycle were smaller in both patient groups than in controls. Radionuclide angiography has been used in assessing left ventricular systolic and diastolic function in patients treated with anthracyclines. Abnormalities in left ventricular filling and ejection rates and ejection fraction during short-term and long-term follow-up have been reported in radionuclide angiography studies^7,30–32 Due to radiation exposure involved in repeated examinations, echocardiography has been recommended to be the primary method in follow-up.³³ There are no previous data on three-dimensionally measured LA and LV volumes in patients after cardiotoxic therapies. The method used in this study could not detect differences between patients and controls in the PFR and PER values calculated from the LA and LV volume data. Thus, the use of these indices does not seem to give additional information in this connection. However, the more accurate noninvasive EF measurement by 3DE is an advantage in the cardiac follow-up of cancer patients. Online 3DE measurements of EF will soon be available in modern echocardiographic machines. This will without doubt increase the reliability of echocardiographic follow-up in patients at risk of deteriorating LV function.

In conclusion, our results showed that LV contractility decreases slowly even years after cardiotoxic therapy necessitating the regular follow-up of these children. 3DE and NT-proANP are effective methods for noninvasive evaluation of cardiac function.

	NOTES

 
This study was supported by the Foundation for Juho-Pekka Saloranta, Finland and the Parent Organization for Children with Heart Disease, Finland.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted August 6, 2001; accepted April 1, 2003.

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