Doxorubicin-induced cardiotoxicity in adult Indian patients on chemotherapy

determine the incidence of doxorubicin-induced cardiotoxicity by serial resting echocardiography in patients on


INTRODUCTION
Anthracyclines represent some of the most commonly used anticancer drugs.Major side effects associated with anthracycline use are bone marrow suppression and cardiac toxicity.Cardiac toxicity is accentuated by increasing age (more than 70 years), female sex, combination chemotherapy, mediastinal radiation, previous cardiac disease, hypertension, liver disease and whole body hypothermia. [1]thracyclines are associated with both acute and chronic cardiotoxicity.Chronic cardiotoxicity in the form of congestive cardiac failure is dose dependent and occurs 4-8 weeks after last anthracycline dose, though it may occur during treatment or years later. [2]reatment with doxorubicin may necessitate lifelong cardiac monitoring.The exact causal mechanism of of cardiac dysfunction increases steeply after a cumulative dose of 450-550 mg/m 2 of doxorubicin is reached, it is not known whether lower cumulative doses also lead to significant cardiac dysfunction warranting very close monitoring.
This study was planned as a preliminary investigation to see whether echocardiography can detect cardiac dysfunction in patients on treatment with doxorubicin and also if there are any identifiable risk factors for cardiac toxicity in Indian patients.

maTeRIals aND meThODs
All newly diagnosed patients aged more than 15 years who were administered doxorubicin for the first time and who gave informed consent were enrolled in the study.All patients were questioned for recent history of hypertension, mediastinal or chest wall irradiation and cardiac or liver disease.Body mass index (BMI) and Karnofsky performance status of all patients were recorded at baseline.A detailed examination of cardiovascular system was done at baseline and at each follow-up.Renal function tests, liver function tests, 12-lead ECG, chest X-ray and echocardiography were done at baseline, at 300 mg/m 2 and at 400-450 mg/m 2 cumulative doses of doxorubicin.During echocardiography, fractional shortening and ejection fraction were evaluated, besides other routine parameters.while ejection fraction was calculated by M-mode and modified Simpson's formula.In order to reduce inter-obser ver variability, echocardiography was performed by the same physician for each patient at different time points.Intra-observer variability was reduced by taking the mean of three readings during each echocardiography.
All patients included in the study had left ventricular ejection fraction (LVEF) greater than 50% at baseline.Patients with history of coronary artery disease who had regional wall-motion abnormalities at baseline echocardiography or had an acute coronary syndrome within 1 year of cancer diagnosis were excluded from the study.
This study was approved by the ethics committee of the institute.

Statistical analysis
Subclinical cardiac dysfunction was defined as fall of ejection fraction .10%during follow-up echocardiography at 300 mg/m 2 and/or 400-450 mg/m 2 .This was based on the published guidelines on monitoring for doxorubicininduced cardiotoxcity. [6,12]

ResUlTs
Thirty-eight patients were enrolled in the study, from January 2000 to June 2001.Eight patients were excluded as they did not receive full course of chemotherapy due to progression of disease.Thirty patients received at least 300 mg/m 2 of doxorubicin, while 14 patients received more than 400 mg/m 2 cumulative dose of doxorubicin.
The baseline characteristics of 30 patients are shown in Table 1.
The chemotherapeutic regimens used according to different diagnoses are shown in Table 2. Twenty (66.7%) patients received regimens that included both cyclophosphamide and adriamycin.The most common dose of adriamycin used was 50 mg/m 2 per cycle of chemotherapy.The schedule of administration of doxorubicin was similar in all patients.All patients received intravenous boluses    of doxorubicin over 10 minutes.Three patients had postponement of cycle of chemotherapy by 1 week due to neutropenia.However, all 30 patients completed the designated number of cycles of chemotherapy according to their protocol.
The prevalence of various risk factors is shown in Table 3.
The most commonly associated risk factor was the concomitant use of cyclophosphamide (66.7%).

DIsCUssION
It is a well-known fact that incidence of cardiac dysfunction rises steeply if cumulative dose of doxorubicin exceeds 550 mg/m 2 .However, very few studies have evaluated development of asymptomatic cardiac dysfunction in the lower cumulative dose range.The present study was aimed to find the incidence of both subclinical and clinical cardiac dysfunction at lower cumulative dose range, viz., 300 to 450 mg/m 2 , by serial echocardiographic measurement and identify any known risk factors associated with cardiac dysfunction.
The incidence of clinically diagnosed doxorubicin-induced congestive heart failure was 3% in our study and is in general agreement with the range of 0.4% to 9% reported by others. [13,14]Though the incidence of congestive cardiac failure was low, incidence of subclinical cardiac dysfunction in our study was high, viz., 27% (8 of the 30 patients).This observation is consistent with studies that have evaluated subclinical cardiac dysfunction.Palmeri et al, [9] in their group of 48 patients that received a mean dose of doxorubicin of 338 mg/ m 2 found that 63% of their patients had some fall in LVEF as measured by rest and exercise radionuclide angiography.Similarly Dresdale et al., [10] in 87 asymptomatic patients that received .430mg/ m 2 of doxorubicin found abnormal LVEF at rest by radionuclide angiogram in 21% of patients.Exercise studies in their study identified an additional 31% of patients.Mohta et al., [15] in pediatric patients observed that 30% of the patients had significant cardiac dysfunction on echocardiographic evaluation at a mean cumulative dose of 365 mg/m 2 .Similarly Agarwala et al., [11] observed that 40% of children undergoing doxorubicin-based chemotherapy developed subclinical cardiac dysfunction at a cumulative dose of 180-200 mg/ m 2 .
Cumulative dose of doxorubicin is the single most important determinant of cardiac toxicity.Lefrak et al., [16] in their study found that incidence of congestive cardiac failure rose to unacceptably high levels when cumulative dose of drug exceeded 550 mg/m 2 , viz., from 4% at 500-550 mg/m 2 to 18% at 551-600 mg/m 2 and to 36% at a dose of 601 mg/ m 2 or more.Von Hoff et al., [17] found that cumulative probability of developing drug-induced heart failure was 0.03 at 400 mg/ m 2 , 0.07 at 550 mg/m 2 and 0.18 at 700 mg/m 2 .In the present study, at 300 mg/m 2 cumulative dose of doxorubicin, 16% developed subclinical cardiac dysfunction; and at 450 mg/ m 2 , 28.8% of patients develop cardiac dysfunction.This difference did not reach statistical significance possibly due to the small size of the study population (χ 2 5 0.26, P .0.1).
The present study found statistically significant association of concomitant use of doxorubicin and cyclophosphamide with cardiac dysfunction (regression coefficient 5 3.22, P 5 0.048).Similar inference was drawn by Minow et al. [13] and von Hoff et al., [17] in their studies, and it is now standard practice to use lower cumulative dose ceiling in patients exposed to both cyclophosphamide and doxorubicin.
Malnutrition has also been identified as a risk factor for doxorubicin-induced cardiotoxicity.A study by Obama et al., [18] found that cardiac toxicity was more in those children that were malnourished (P ,0.05).Similarly Mohta et al., [15] in Indian pediatric cancer patients observed that children that developed cardiac dysfunction had significantly lower height and weight for age compared to those that remained normal.Though we did not do a formal nutritional assessment in our patients, we analyzed the incidence of cardiac dysfunction in patients with lower BMI (,20 kg/ m 2 ) as a surrogate marker of nutritional status.Patients with BMI ,20 kg/m 2 were shown in our study to have increased risk of cardiac dysfunction, though the association did not reach statistically significant level, probably due to the small sample size (regression coefficient 5 20.432, P 5 0.07).How poor nutritional status affects cardiotoxicity is not clear, though it has been reported that micronutrients like carnitine, [19] selenium [20] and vitamin E [21] have ameliorated cardiotoxicity of anthracyclines.
In our study, 6 (20%) patients had medical history of coronary artery disease.All 6 patients had LVEF greater than 50% at baseline with no regional wall motion abnormalities in echocardiogram.Two out of 9 patients with doxorubicin-induced cardiac dysfunction had coronary artery disease.Multiple logistic regression analysis showed that cardiac disease as a risk factor almost reached statistical significance in contributing to doxorubicin-induced cardiotoxicity in our patients (regression coefficient 5 4.088, P 5 0.07).The results are similar to those in the studies by von Hoff et al. [17] and Minow et al., [13] who found that patients with preexisting cardiac disease had increased probability of developing cardiac dysfunction due to doxorubicin.
The present study due to its small sample size did not find hypertension, advanced age, receiving mediastinal irradiation, sex and performance status to be risk factors for cardiotoxicity.
The high incidence of subclinical cardiac dysfunction in our patients reinforces the need for strict monitoring of patients on doxorubicin during treatment.