- © 1999 by American Society of Clinical Oncology
Indium-111–Antimyosin Scintigraphy in the Early Detection of Heart Damage After Anthracycline Therapy in Children
- L.C.M. Kremer,
- M.M.C. Tiel-van Buul,
- M.C. Ubbink,
- M. Offringa,
- J. Ottenkamp,
- R. Valdés Olmos and
- P.A. Voûte
- From the Departments of Pediatrics and Nuclear Medicine, Academic Medical Center, Emma Children's Hospital, University of Amsterdam, and Department of Nuclear Medicine, Netherlands Cancer Institute, Amsterdam, the Netherlands.
- Address reprint requests to L.C.M. Kremer, MD, Department of Pediatrics, Academic Medical Center, Emma Children's Hospital, University of Amsterdam, G8-259, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; email l.c.kremer{at}amc.uva.nl
Abstract
PURPOSE: To determine the value of indium-111–antimyosin (111In-AM) scintigraphy in the early detection of myocardial damage in children treated with doxorubicin.
PATIENTS AND METHODS: Twelve planar scintigrams were made of eight patients (seven children and one young adult; mean age, 12 years). Three scans were obtained before doxorubicin therapy in three patients, and nine scans were obtained during doxorubicin therapy in seven patients. The heart-to-lung ratio (HLR) was calculated. Left ventricular function was assessed by echocardiography before and during therapy by measuring the fractional shortening (FS).
RESULTS: The HLR of the three baseline scans was below 1.5, within the normal range for adults. Six of the seven patients whose scans were obtained during chemotherapy had abnormal HLR values (> 1.5). One patient had severe myocyte damage and showed an early increase in the HLR (2.3) after a cumulative doxorubicin dose of 150 mg/m2. The FS measured by echocardiography was normal throughout therapy, and the final cumulative dose of doxorubicin was 450 mg/m2. This patient developed fatal clinical heart failure 3 months after completion of chemotherapy. In one patient, who was pretreated with the cardioprotective agent dexrazoxane, the HLR remained within normal limits during therapy.
CONCLUSION: 111In-AM scintigraphy seems to be suitable to detect early myocardial damage after a cumulative doxorubicin dose of 150 mg/m2 in children and may be useful for identifying children who are at increased risk of developing cardiac sequelae.
DESPITE THE FIRMLY established early and late cardiotoxic side effects of anthracyclines, these drugs are among the most widely used agents for the treatment of childhood cancer.1,2 The incidence and severity of clinical and subclinical cardiac damage after anthracycline therapy increases with increasing cumulative dose, additional radiotherapy, and female sex.3 Moreover, children seem to be more susceptible than adults to the cardiotoxic effects of anthracycline therapy, although there is considerable variation in the individual susceptibility to these side effects.4
Conventional methods, such as radionuclear angiography and echocardiography, are not suitable for investigating early cardiac damage because they are not sensitive enough; ie, a critical number of cells may be damaged before the functional myocardial impairment is detected.5 Yet, early identification of children at risk for cardiac damage is essential, because subsequent preventive measures can limit further myocardial damage. In this setting, indium-111–antimyosin (111In-AM) scintigraphy may be of diagnostic use, because it allows noninvasive detection of myocardial damage in vivo. The binding of this antibody to intracellular myosin takes place only when the sarcolemma is disrupted owing to cell damage.6 A study of rats treated with doxorubicin showed a progressive increase in myosin uptake with increasing severity of myocardial damage. A strongly positive correlation was found between the intensity of myocardial uptake and the loss of contractile function. Immunohistochemical staining showed that 111In-AM was localized exclusively in injured myocytes.7 Studies with adult patients showed that the intensity of 111In-AM uptake was related to the cumulative dose of doxorubicin and that 111In-AM uptake preceded changes in the ejection fraction.8-10
There have been no studies of 111In-AM uptake in children and young adults treated with anthracyclines. We performed a pilot study involving eight patients who were treated with doxorubicin to determine whether 111In-AM scintigraphy can be used to detect early cardiac damage during chemotherapy in children and in young adults.
PATIENTS AND METHODS
Patients
Eight patients with a tumor eligible for doxorubicin treatment were included in the study: seven children and one young adult, with a mean age of 12 years (range, 1 to 25 years). The patient characteristics are listed in Table 1. Additional therapy with cyclophosphamide (maximum dose, 8,400 mg/m2) and ifosfamide (maximum dose, 7,800 mg/m2) was given to patients with Ewing's sarcoma and Burkitt's lymphoma. One patient (no. 5) was cotreated with dexrazoxane, a cardioprotective agent. The study was approved by the hospital ethics committee.
Clinical Data
Scintigraphy
111In-AM planar scintigraphy of the thorax in anterior-posterior projection was undertaken on one or two occasions during the course of chemotherapy, before chemotherapy, or 3 weeks after the administration of doxorubicin. 111In-AM was prepared by adding 92 MBq (2.5 mCi) [111In]indium chloride to a flacon containing 0.5 mg of R11-D10-Fab diethylenetriamine penta-acetic acid (Mallinckrodt Medical B.V., Petten, the Netherlands). The amount of radioactivity used depended on the patient's age: 40 MBq was used for patients younger than 10 years, 60 MBq for patients aged 10 to 14 years, and 80 MBq for patients older than 14 years. Scintigraphy was performed 48 hours after infusion of AM. We used a large-field-of-view Diacam gamma camera (Siemens, Erlangen, Germany) equipped with a medium-energy collimator and a 20% window set around both peaks of 111In at a preset time of 10 minutes. Scans were stored in 128 × 128 frames for subsequent analysis. The scintigrams were interpreted quantitatively by an experienced nuclear physician unaware of the patient's condition and echocardiographic results. Regions of interest for heart and lungs were drawn, and a heart-to-lung ratio (HLR) was calculated as the average counts per pixel in the myocardium divided by the average counts per pixel in the lungs.11 The mean value of three separate HLR evaluations was used as the HLR value of an 111In-AM scintigram.
Echocardiography
Echocardiograms were obtained by a pediatric cardiologist and a technician before and after 3 weeks of doxorubicin administration
as a part of the treatment protocol, using 3.5- and 5-MHz transducers. All echocardiograms were recorded on videotape, and
fractional shortening (FS) was measured by one observer who did not know the results of the 111In-AM scintigraphy and who was unaware of the patient's condition. The FS of the left ventricle was calculated according to
the formula: 
where LVEDD is left ventricular end diastolic diameter, and LVESD is left ventricular end systolic diameter.
RESULTS
The scintigraphic and echocardiographic results are shown in Table 2. Three patients (patients no. 6, 7, and 8) underwent baseline 111In-AM scintigraphy; their HLRs were 1.49, 1.5, and 1.51, respectively. Patients no. 1, 2, 3, and 8 underwent 111In-AM scintigraphy only once because treatment was completed (patient no. 1) or because of progressive disease (patients no. 2 and 8) or radiotherapy of the thorax (patient no. 3). The HLR of patient no. 6 increased substantially from 1.49 before doxorubicin therapy to 2.3 at scintigraphy performed 3 weeks after a cumulative dose of 150 mg/m2 doxorubicin, an increase of more than 50% of the baseline value. The FS was normal throughout therapy. The final cumulative dose of doxorubicin was 450 mg/m2. Unfortunately, 3 months after she finished chemotherapy, with her cancer in complete remission, she developed heart failure and died within a week. No autopsy was performed. The increase in the HLR between two scans in patients no. 4 and 7 was 0.29 in both, with a comparable time interval. The FS did not change in these patients, and neither had evidence of clinical heart failure at the time of the last follow-up (6 months after completion of cytotoxic therapy). The HLR of patient no. 5, who was cotreated with dexrazoxane, did not increase at all after anthracycline therapy.
Summary of Scintigraphic and Echocardiographic Results
In none of the patients did the FS decrease by more than 10%, compared with the baseline value, or decrease to an absolute value below 30%. Therefore, the treatment regimen of doxorubicin was not changed. In patient no. 1, it was not possible to measure the baseline FS reliably, because of pericardial exudate. No echocardiographic follow-up was obtained for patients no. 2 and 8 because of progressive disease.
DISCUSSION
This pilot study indicates that 111In-AM can play a role in the early detection of cardiac damage due to anthracycline therapy in children and young adults. The HLR values obtained by 111In-AM scintigraphy for three patients before therapy were comparable with the normal values for adult patients.12 During therapy, in seven patients, the measured HLR was above these normal values. In adults, myocyte damage has been detected by 111In-AM scintigraphy atintermediate cumulative doses of doxorubicin of 240 to 300 mg/m2.9 In our study, we detected an early elevated HLR after cumulative doses of 120 and 150 mg/m2. Patient no. 6 had an HLR of 2.3 after a cumulative dose of doxorubicin of 150 mg/m2. Three months after finishing the course of therapy with 450 mg/m2 doxorubicin, she developed clinical heart failure and died. The left ventricular FS measured by echocardiography remained normal until the end of treatment. This case confirms the results of studies with adults: a high HLR (above 1.9) increases the risk of cardiotoxicity, defined as a decrease in ejection fraction or clinical heart failure.8-10 The HLR did not increase in the one patient who was cotreated with dexrazoxane, a cardioprotective agent. In this patient, both HLR values (1.43 after 150 mg/m2 and 1.36 after 225 mg/m2) were within the normal range for adults and below the three baseline values. Our results suggest that 111In-AM scintigraphy can be used to evaluate early cardiac damage associated with different treatment schedules and to assess the effectiveness of cardioprotective agents in children receiving anthracyclines. Lopez et al13 described a randomized trial in which adults were treated with epirubicin, with or without dexrazoxane, and cardiotoxicity was monitored by 111In-AM scintigraphy and radionuclide angiography. With 111In-AM scintigraphy, they found a significant difference between the two treatment groups in an early stage of anthracycline therapy, but not when they measured the left ventricular ejection fraction by multigated radionuclide angiography.
In this study, we found evidence of myocardial injury as measured by 111In-AM scintigraphy in patients with a normal FS. These results are consistent with endomyocardial biopsy findings and serum cardiac troponin concentrations measured in patients receiving anthracycline therapy.14-17
In 1983, Isner et al14 described histologic signs of anthracycline cardiotoxicity in 52% of their patients, even although these patients did not show changes in heart function. A recent publication by Herman et al15 demonstrated that cardiac troponin T (cTnT) concentrations were elevated in rats after doxorubicin treatment. The increased serum concentrations of cTnT occurred at a time when there was only minimal myocyte damage. Lipshultz et al16 found increased concentrations of cTnT in children treated with doxorubicin; the magnitude of this increase was positively correlated with echocardiographic abnormalities of the left ventricule 9 months later. In adult patients, Missov et al17 found an increase in cardiac troponin I concentration in the absence of a decreased left ventricular ejection fraction.
Lipshultz et al18 pointed out that the ejection fraction and FS were of limited value in detecting anthracycline cardiotoxicity. Furthermore, functional deterioration after damage to a critical number of myocytes may be masked by several factors, including reserve capacity and compensatory mechanisms. For these reasons, conventional methods, such as echocardiography and radionuclide angiography, are unsuitable for the early detection of treatment-induced cardiac damage.
The results of this pilot study suggest that 111In-AM scintigraphy can detect early myocardial damage before conventional methods detect cardiac dysfunction in children treated with anthracyclines. In future clinical trials, 111In-AM scintigraphy can be used to identify patients at risk of subsequent cardiac sequelae and to measure the effect of cardioprotective agents.
Acknowledgments
Supported by the Pediatric Cancer Research Foundation, Amsterdam, the Netherlands.
- Received August 17, 1998.
- Accepted December 7, 1998.
