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Brief Reports

Indian Pediatrics 2002; 39:549-555

Anthracycline Associated Cardiac Toxicity in Children with Malignancies

R. Mohta
A. Saxena*
Y. Jain
S. Gupta
V. Thavaraj
Sunil Narain
L.S. Arya

From the Departments of Pediatrics and Cardiology*, All India Institute of Medical Sciences, New Delhi 110 029, India.

Correspondence to: Dr. L.S. Arya, Professor, Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi 110 029, India.

E-mail: [email protected]

Manuscript received: June 11, 1998;

Initial review completed: September 28, 1998;

Revision accepted: September 24, 2001.

The Anthracyclines, doxorubicin and daunorubicin, are effective antineoplastic agents used widely in pediatric chemotherapeutic regimes for the past 20 years(1). Unfortunately, repetitive administration of anthracyclines in humans is associated with cardiomyopathy, the dose limiting toxicity of this drug, which leads to congestive heart failure (CHF)(2). Attempts have been made to identify risk factors for cardiotoxicity of anthracyclines. While a relationship between the cumulative dosage and cardiotoxicity has been established(3), age, sex, nutiritional status, dose intensity, mediastinal irradiation, preexisting cardiac disease and hypertension have been variably implicated(4-10).

The Cardiology Committee of Children Cancer Study Group has published guidelines for cardiac monitoring of children during and after anthracycline therapy. It recommends serial monitoring of these patients using echocardiography and radionuclide angiography to detect cardiac toxicity(11). Since there was a need to study cardiotoxicity of anthracyclines in our country, we decided to undertake this study to ascertain the prevalence of cardiotoxicity due to anthracycline therapy and the risk factors associated with it.

Subjects and Methods

Children with malignancies who received anthracyclines as a part of their chemotherapeutic regime and who were enrolled at the Pediatric Oncology Clinic at the All India Institute of Medical Sciences, New Delhi from June 1, 1994 to May 30, 1996 were included in the study. A total of 47 patients were included in the study; the malignancies included acute lymphoblastic leukemia (ALL) in twenty two, Hodgkin disease in eighteen, retinoblastoma in three, neuroblastoma in three and non-Hodgkin lymphoma in one. Only children who received anthracyclines at an age less than 14 years and had received a minimum cumulative dose of 160 mg/m2 were eligible for this study. The cardiac evaluation was done at least 3 months after the last dose of anthracyclines to rule out any acute myocardial dysfunction. Children with preexisting cardiac disease, history of having received mediastinal or spinal irradiation, mitotraxone, amasacarine, cyclophosphamide (>40 mg/kg/day) or actinomycin D were excluded from the study. Cardiac assessment was done after ensuring a hemoglobin level of more than 10 g/dl.

A detailed evaluation of clinical features and symptomatology was performed on all patients. Nutritional status was ascertained by recording the heights and weights of children at the beginning of therapy and at the time of cardiac evaluation along with calculation of their respective weight for height. All figures were calculated as a percentage of the 50th percentile for the respective age and sex of affluent Indian children(12).

A chest X-ray (PA view) was performed in each patient to evaluate the cardiothoracic index

MRD + MLD/ID

(MRD: maximum diameter of right side of cardiac shadow, MLD: maximum diameter of left side of cardiac shadow, ID: internal diameter of thorax). A 12 lead EKG was performed in each patient. Myocardial function was assessed by echocardiography on the Helwett Packard HP Sonos 1500 echocardiography machine with 3.0 or 5.0 mega hertz transducer. Measurements were made according to the recommendations suggested by the American Society of Echocardiography. Diastolic and systolic dimensions of left ventricle were measured using M-mode echocardiography.

Fractional Shortening (FS) was calculated from these as follows:

FS = LVIDd - LVIDs/LVIDd

LVIDd: left ventricular diameter in end diastole.

LVIDs: left ventricular diameter in end systole.

Left ventricular endsystolic (LVSV) and enddiastolic volumes (LVDV) were measured by 2-D echocardiography using modified Simpson’s technique. Ejection fraction (EF) was calculated from these volumes as follows:

EF = LVDV - LVSV/LVDV

Left ventricular systolic time interval was recorded from the M-mode trace of aortic valve with simultaneous ECG recording. The systolic time intervals recorded were pre-ejection period (LVPEP) and ejection time (LVET). These measurements were used to calculate left ventricular systolic time interval (STI) as follows:

STI = LVPEP/LVET

Significant deterioration in cardiac function was defined as an ejection fraction £55% as per guidelines of Cardiology Committee of the Children Cancer Study Group, USA and control values from our center. Children who showed myocardial dysfunction were compared with those who did not develop dysfunction for various risk factors and for various cardiac function tests. In risk factors, continuous variables were evaluated by pooled t-tests while non continuous variables were evaluated by Pearson Chi-Square tests. The risk factors that were compared were sex, age at diagnosis, total dose of anthracyclines, duration since completion of therapy, type of malignancy and nutritional status. The relationship between T index, EKG findings and left ventricular function tests were also evaluated by pooled t-tests.

Results

Fourteen of the 47 (29.7%) patients had significant cardiac dysfunction on echocardiographic evaluation. Six of 23 patients receiving doxorubicin (26.0%) and 8 of 24 receiving daunorubicin (33.3%) developed cardiotoxity. Their mean ejection fraction was 44.6% with a range of 37.5- 52.6%. Only 2 of these 14 patients had symptoms referable to cardiovascular system in the form of palpitations and dyspnea on exertion. None of these patients had congestive heart failure or required any drug therapy for cardiac dysfunction.

The age group of the patients at the time of starting therapy ranged from 12 months to 168 months. There was no significant difference in the demographic profile of patients who developed cardiac dysfunction and those who did not (Table I). Forty two of the 47 children in the study group were males; eleven (26.2%) developed cardiac dysfunction. Of the 5 girls, 3 (60%) developed cardiac dysfunction. Pateints with malignancies that require higher doses of anthracyclines as a part of their chemotherapeutic regime tended to develolp cardiac dysfunction more commonly. Among children with ALL, seven (31.8%) developed cardiac dysfunction after having received 360 mg/m2 of daunorubicin as compared to only two (11.1%) of children with Hodgkin disease who received only 200 mg/m2 of doxorubicin (p = 0.0286).

Table I__Characterstics of the 47 Children Who Received Anthracyclines
	
Parameter
Cardiac
dysfunction
(n = 14)
No cardiac 
dysfunction
(n = 33)
p value
Age (mo)
78.7(12-151)
79.6(29-168)
NS
Sex
  Male (n = 42)
11(26.2%)
31(73.8%)
NS
  Female (n = 5)
3(60%)
2(40%)
Malignancy
  ALL (n = 22)
7(31.8%)
15(68.2%)
0.0286
  Hodgkin’s Disease (n = 18)
2(11.1%)
16(88.9%)
  Others (n = 7)
5(71.4%)
2(28.6%)
Drug used
  Doxorubicin (n = 23)
6(26%)
17(74%)
NS
  Daunorubicin (n = 24)
8(33.3%)
16(66.7%)
Dosage (mg/m2)
  Doxorubicin
305(160-660)*
205.8(160-360)*
0.0054
  Daunorubicin
360
360
Duration since Therapy (mo)
19.2(13-59)*
15.36(3-48)*
NS
NS = Not significant; * Figures indicate range.	

 

Among all children receiving doxorubicin, the mean dose used in those who developed cardiomyopathy was 370 mg/m2 as compared to 205 mg/m2 in those who remained normal. However, the doxorubicin drug dosage used among patients who developed cardio-myopathy ranged from 160 mg/m2 to 660 mg/m2. The present study could not demonstrate the same effect for daunorubicin since all children with ALL had received a total cumulative dose of 360 mg/m2 of daunorubicin. Cardiac dysfunction was detected 3-59 months following discontinuation of therapy (mean 19.2 months) by a single echocardiogram.

As shown in Table II, the patients who developed cardiac dysfunction following anthracycline therapy had significantly lower height for age and weight for age at the beginning of therapy. Weight for height was also considerably lower in these patients but it did not achieve statistical significance (p = 0.623).

Table II__Nutritional Status of the Children in the Study Group
	
 
Cardiac dysfunction (n = 14)
Normal cardiac function (n = 33)
 
 
Mean
SD
Mean
SD
p value
Beginning of therapy
  Height for age
95.9%
(84-106)*
7.15
99.9%
(89-125)*
4.65
0.0269
  Weight for age
85.5%
(63-118)*
14.65
93.5%
(75-128)*
10.94
0.0441
  Weight for height
88.6%
(62-114)*
14.33
94.69%
(83-113)*
7.43
0.0623
At the time of evaluation
  Height for age
95.9%
(76-107)*
8.12
97.2%
(90-109)*
4.39
NS
  Weight for age
91.9%
(72-112)*
11.95
95.0%
(62-123)*
13.28%
NS
  Weight for height
97.4%
(81-111)*
9.02
98.0%
(77-116)*
10.79%
NS

All figures in % are derived from the 50th centile for the respective age and sex of affluent Indian children(12).
NS = Not significant; * Figures indicate range.

 

Patients with cardiac dysfunction had higher heart rates (mean = 106/min) compared to those who remained normal (mean 97.9/min), however, this was not statistically significant (p = 0.0768). The QTc and PR intervals were not significantly different in the two groups. The QRS complex axis and duration were not statistically different in the two patients groups. However, QRS amplitude (algebraic sum in six limb leads) was significantly lower in abnormal group (mean 72.64) compared to normal group (mean 95.09) (p = 0.007). R/S ratio in leads VI and V6 and ST segment changes did not correlate with cardiac dysfunction. The cardiothoracic index also did not correlate with cardiac abnromality. Fractional shortening correlated very strongly with ejection fraction abnormality (p <0.001) (Table III). Systolic time intervals were however of no significance in predicting cardiac abnormality.

Table III__Results of Echocardiographic Evaluation
	
 
Cardiac toxicity(n = 14)
Normal (n = 33)
 
Mean
SD
Mean
SD
P Value
Fractional shortening
0.28
0.03
0.36
0.06
< 0.0001
 
(0.214-0.359)
 
(0.160 - 0.483)
Systolic time interval
0.12
0.06
0.15
0.16
NS
 
(0.015 - 0.230)
 
(0.037 - 0.970)
Ejection fraction (%)
44.6
3.8
66.4
2.7
< 0.001
 
(0.375 - 0.526)
 
(0.560 - 0.800)
NS = Not significant; * Figures indicate ranges

Discussion

In our study, 29.7% of children receiving anthracyclines developed significant cardiac dysfunction at a mean cumulative dose of 365 mg/m2. These patients had ejection fractions ranging from 37.5% - 52.6% with a mean of 44.6%. A 13% incidence of cardiac dysfunction was reported in 766 patients(11). Thus, it appears that our patients have poor tolerance to cardiac effects of anthracyclines, even in the moderate doses curently being used by us. It has been well established that cumulative doses of anthracyclines being used is the most important risk factor for cardiac toxicity(5,11,13). Patients who developed cardiomyopathy had received a mean dose of 370 mg/m2 doxorubicin compared to 205 mg/m2 in those who remained normal.

Younger age has been reported to decrease cardiac tolerance to anthracyclines(4,11). However, in our study there was no clear evidence of any effect of age on cardiotoxicity. Silber et al.(6) have reported an increased incidence of cardiac toxicity in feamles. In our study 60% females developed cardiac toxicity as compared to 26.2% in males. However, the number of girls screened was so little that no conclusion could be drawn from this data.

Our study suggests further that the poor cardiac tolerance in our patient group could be contributed by their compromised nutritional status at beginning of therapy. The patients who developed cardiomyopathy had significantly lower height for age (95.9%) compared to those who remained normal (99.9%) (p = 0.0269). They also had lower weight for age (85.6% vs 93.5%) (p = 0.441). The weight for height was also considerably lower in patients with cardiotoxicity (88.6% vs 94.69%), but it did not achieve statistical significance (p = 0.0623). One previous study has also reported that poor nutritional status causes poor cardiac tolerance to anthracyclines(7). How poor nutritional status affects cardiotoxity is not clear. Some micronutrient like carnitine(14), selenium(15) and vitamin E(16) have earlier been reported to ameliorate the cardiotoxic effects of anthracyclines. Chest X-ray changes in the form of increased cardiothoracic (CT) index tend to appear late in course of anthracycline therapy(11). In our study also, CT index did not correlate with cardiac toxicity. Decreased QRS voltage and decreased R/S ratio in EKG have been reported to indicate anthracycline cardiotoxicity(17). In our study, there was significantly lower QRS voltage in patients with poorly contracting heart. However, no other findings in EKG was significantly different in the two study groups. Fractional shortening was significantly lower in cardiomyopathy group as expected. Some earlier studies had reported elevation of systolic time interval with cardiotoxity(18). In our study also, systolic time interval increased but not significantly indicating that it is not a very sensitive marker for cardiotoxicity. Evidence of cardiac dysfunction was found as late as 59 months after anthracycline therapy; however, late cardiac status of these children can only be evaluated by careful and longer follow up of this patient group.

From our study, we conclude that there is a significantly higher incidence of cardiotoxicity with anthracycline therapy in our patients compared to published data inspite of moderately lower doses being used currently. However, most of this cardiotoxicity is subclinical. Only 2 out of 14 patients who were detected to have cardiac dysfunction post-therapy were symptomatic. None of these had CHF. How this subclinical toxicity will affect future morbidity and mortality is difficult to predict from this data. The risk factor most strongly associated with anthracycline cardiotoxicity is the cumulative dose of anthracyclines used. However, an important predictor of cardiac tolerance which has emerged from our study is the nutritional status at the time of receiving therapy. Patients developing cardiac toxicity had significantly poorer nutritional status.

Thus, the routine practice of arbitrarily limiting anthracycline dosage to 450-550 mg/m2 is arguable. Careful follow up of cardiac status of patient after 160-200 mg/m2 of anthracyclines is necessary. Dose adjustments in view of increased cardiotoxicity in our patient groups appears to be essential.

Contributors: RM and LSA designed the study, collected and analyzed the data and prepared the manuscript; they will act as guarantors for the paper. YJ helped in data analysis and drafting of the manuscript. AS was responsible for the cardiac evaluation of the study group. SG helped in collecting the data. VT and SN helped in the final drafting of the paper.

Funding: None.

Competing interests: None stated.

 

 

Key Messages

• Subclinical cardiac toxicity is common even after moderately lower doses of anthracyclines.

• Alertness in early identification of cardiotoxicity by echocardiographic evidence, even after administration of 160-200 mg/m2 of anthracyclines, can be expected to evolve better dose adjustment in anthracycline based chemotherapy protocols.

• Children with a compromised nutritional status, as a group, are high-risk cases for development of anthracycline cardiotoxicity.


 References


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