Anthracyclines represent the greatest risk for development of cardiotoxicity. The most common manifestations of anthracycline cardiotoxicity are arrhythmias, cardiac dysfunction (cardiomyopathy, heart failure), pericardial injury and myocardial ischemia. Cardiotoxicity of anthracyclines may develop during the treatment (acute cardiotoxicity) and during the follow-up (chronic and late cardiotoxicity). Clinical efficacy is often limited by associated cardio­toxicity leading to cardiomyopathy that may worsen the patient’s outcome [1].

According to the time of onset, cardiotoxicities are classified into:

1) “Acute”, occurring after a single dose, or a single course, of anthracyclines, with onset of clinical manifestations within two weeks from the end of treatment;

2) “Early onset chronic”, developing within 6 months -1 year. This is the most frequent and clinically relevant form of cardiotoxicity, usually presenting as a dilated and hypokinetic cardiomyopathy leading to heart failure (HF);

3) “Late onset chronic” developing years, or even decades, after the end of chemotherapy [2].

The total cumulative dose is one of the main risk factor for anthracycline-related cardiotoxicity. However, there is no completely safe dose, and so the cardiotoxicity of any given dosage must always be weighed against efficacy of the drug. Treatment duration may also influence the risk of cardiotoxicity during or after therapy and prolonged administration have shown to reduce the severity of cardiac injury. Younger patients are more vulnerable to the cardiotoxic effect of anthracyclines [3].

Various methods have been recommended for monitoring of cardiotoxicity in oncology including Echocardiography (ECHO) and electrocardiography (ECG) which are routinely used. Serial non-invasive surveillance for evidence of cardiotoxicity in patients receiving anthracyclines has centered on the Echocardiographic assessment of left ventricular (LV) systolic function using ejection-phase indices, namely, fractional shortening and ejection fraction. LV shortening fraction and ejection fraction have shown to be valuable clinical predictors of morbidity and mortality in children and adults with malignancies who receive anthracyclines as part of their therapeutic regimen [4].

• Ethical committee- Approved

Method of collection of data (including sampling, procedure, if any)

• A standard proforma will be used to collect patient related data for the study.
• Informed consent will be taken.
• Patients who will receive Doxorubicin >200 mg/m2 as part of treatment protocol will be randomly allocated to the study. Demographic details of these patients will be entered in the proforma. Each patient was assessed clinically (History, Pulse rate, Blood pressure) along with ECG, ECHO and NT-pro BNP prior to initiation of chemotherapy, after completion of 200 mg/m2 of Doxorubicin, 3 months and 6 months after chemotherapy.
• Patients were observed for developments of signs and symptoms of CHF, cardiomyopathy characterized by decrease in the LVEF that was either global or more severe in the septum, decline in the LVEF of at least 5% to less than 55% with signs or symptoms of CHF, or a decline in LVEF of at least 10%, to below 55% without signs or symptoms which would suggest cardiotoxicity.

Inclusion criteria

• Age more than 18 years and less than 70 years.
• Patients with any malignancy who will receive > 200 mg/m² of Doxorubicin as part of the treatment protocol.

Exclusion criteria

• History of valvular or coronary cardiac diseases.
• Prior exposure to anthracyclines.
• Prior exposure to irradiation to the mediastinum.
• Patient with LVEF <55 % in the baseline ECHO

Statistical analysis- The Statistical software namely SPSS 18.0, and R environment ver.3.2.2 were used for the analysis of the data and Microsoft word and Excel have been used to generate graphs, tables etc.

Statistical methods: Descriptive and inferential statistical analysis has been carried out in the present study.

Results on continuous measurements are presented on Mean ± SD (Min-Max) and results on categorical measurements are presented in Number (%). Significance is assessed at 5 % level of significance.

Mean ± SD: 44.33±11.93

Table-2: Gender distribution of patients studied.

Among the study population of 80 patients, only 11 patients had history of co-morbid conditions which included 6 hypertensive patients, 4 patients with diabetes mellitus and one patient with Congenital heart Disease- Atrial Septal Defect- Post surgical closure. All these patients were on regular medication for these respective illnesses. Table 3 gives the BSA distribution of the study population. Average height was 157.16 cm and average weight was 55.91 kg in the study population of 80 patients.

Table-3: BSA- distribution of patients studied.

In the present study majority of the patients were Stage III accounting to almost 62.5% of the total study population. There were around 19 patients with Stage IV disease which was 23.8%. The Stage distribution of the study population is mentioned in Table 4.

Table-4: Stage of disease distribution of patients studied.

In the present study the maximum numbers of patients were carcinoma breast patients constituting almost 60% of the total study population. The next common diagnosis was Non Hodgkins Lymphoma. The details regarding the diagnosis distribution is mentioned below in Table 5.

Table-5: Diagnosis- distribution of patients studied.

None of the patients developed any cardiac symptoms during or after the planned chemotherapy. There was no drop in Left Ventricular Ejection Fraction on serial ECHO during the period of the study. Total of 4 patients had upfront BNP values > 300 pg/ml and 4 patients with moderate elevation of NT-pro-BNP (200-300 pg/ml), however none of these patients developed acute or early chronic cardiotoxicity.

14 patients had serially increasing values of NT-pro-BNP in the 6 months follow-up, however none of these patients developed acute or early chronic cardiotoxicity. Whether these patients will develop late chronic cardiotoxicity needs to be confirmed with a longer follow-up. NT-pro-BNP distribution and mean values are mentioned in Table 9 and Table 10.

Table 9: BNP (pg/ml)- Assessment from baseline at different study time points of patients studied.

Table-10: BNP (pg/ml)- Comparison from baseline at different study time points of patients studied

Anthracyclines are among the most commonly used chemotherapy drugs. However, their efficacy is sidelined by potential life-threatening cardiotoxicity. Anthracy-cline induced cardiotoxicity is potentiated when the cumulative dose of doxorubicin exceeds 300 mg/m². Symptomatic heart failure is rare with cumulative dose of 240 mg/m² [9].

Among these regimens, AC regimen was the most commonly used regimen as majority of study population were cases of Carcinoma breast. In the present study median number of cycles was 4, with 48 patients receiving 4 cycles of chemotherapy and the rest receiving 6 cycles.

Sandri et al used High dose chemotherapy every 28 days for 1-3 cycles depending on the specific chemotherapy schedule. All patients underwent reinfusion of autologous peripheral blood progenitor cells during each course of High dose chemotherapy.

The mean cumulative dose of doxorubicin was 267.75 mg/m² in the present study. Only 5 out of the 80 patients received doses more than 300 mg/m². Among the study population of 80 patients , only 11 patients had history of co-morbid conditions which included 6 hypertensive patients, 4 patients with diabetes mellitus and one patient with Congenital Heart disease – Atrial Septal Defect - Post surgical closure. All these patients were on regular medication for these respective illnesses.

None of the patients in the present study developed any cardiac symptoms or a drop in the Left Ventricular Ejection Fraction or shortening fraction on serial ECHO during the period of the study. As none of the patients in the study developed cardiotoxicity, correlation between ECG changes and NT-pro-BNP values could not be done.

However in the study done by Sandri et al, seventeen patients (33%) had persistently increased NT-pro-BNP, 19 patients (36%) had only transient increases (concentrations went back to baseline at 72 h), and 16 (31%) had no increases [mean (SD) values at 72 h, 1163 (936) ng/L vs 185 (101) ng/L vs 39 (19) ng/L, respectively; P <0.0001].

Only patients with persistently increased NT-pro-BNP had a significant worsening of the left ventricular diastolic indexes from baseline to 12 months [ratio of peak early to peak late flow velocities from 1.42 (0.33) to 0.78 (0.11)] isovolumetric relaxation time from 90 and of the left ventricular ejection fraction [from 62.8 to 45.6] [10]

In one study done by Horacek et al, twenty-six adult patients (mean age 46.2±12.4 years, 15 males) were studied. They were treated with 2–6 cycles of chemotherapy (CT) containing anthracyclines in the total cumulative dose of 464.3±117.5 mg/m². Cardiac evaluation with biochemical mark­ers — “N-terminal pro brain natriuretic peptide” (NT-pro-

24h after each NHDC cycle along with Left ventricular (LV) function was assessed by echocardiography at baseline, every two NHDC cycles, at the end of chemotherapy, and at 3-, 6- and 12-month follow-up. According to NT-pro-BNP behaviour, patients were divided into two groups with group A (n-50) with normal (n-23) or transiently elevated NT-pro-BNP levels (n-27), and group B (n-21) with persistently elevated NT-pro-BNP levels.

At 12-month follow-up, two patients experienced dyspnoea (after the end of chemotherapy) with clinical evidence of heart failure, and two additional patients developed supraventricular arrhythmias (during chemotherapy). All these four patients belonged to group B (with persistent NT-pro-BNP elevation). Hence the author concluded that serial measurements of NT-pro-BNP may be a useful tool for the early detection of patients treated with NHDC at high risk of developing cardiotoxicity [12].

In the present study, as none of the patients developed cardiotoxicity, correlation with NT-pro-BNP levels was not possible. There were 4 patients who had very high values of NT-pro-BNP (>300 pg/ml) and 4 patients with moderate elevation of NT-pro-BNP (200-300 pg/ml) prior to the initiation of chemotherapy. 14 patients had serially increasing values of NT-pro-BNP in the 6 months follow-up. However there was no development of acute or early chronic cardiotoxicity in any of these patients during the period of the study.

Hence it can be safely concluded that upfront elevated NT-pro-BNP or serially raising values of NT-pro-BNP cannot be taken as a marker for development of acute or early chronic cardiotoxicity associated with adminis-tration of doxorubicin. The correlation of NT-pro-BNP with late chronic cardiotoxicity cannot be commented in this study in view of the short follow-up of 6 months.

1. Patients were followed up only for a period of 6 months. Patients are being kept on longer follow-up of upto 3 years to watch for development of late chronic cardiotoxicity and the updated result will be published in due course of time. If patient develops late chronic cardiotoxicity during follow-up, then the correlation with upfront and serial NT-pro-BNP values can be done.

Author take this opportunity to thank a number of people who have been an integral part in the completion of this study. Author would like to offer utmost and heart-felt thanks and respect to professor, teacher and guide Dr. Shashidhar V.K, Professor and Head of department of Medical Oncology, Vydehi Institute of Medical Sciences and Research Centre, Bangalore, for lending his constant support, encouragement, motivation and invaluable guidance during the preparation of the manuscript and for analysis of the data.

Author is thankful to Dr. Manjunath I N and Dr. Veerendra for their support in times of need or otherwise. They helped in the follow-up of the 80 patients and also for getting required investigations during the follow-up period. Author would like to profusely thank all the colleagues for unflinchingly sharing the work and providing help which was much needed. Author would also like to extend gratitude towards radiation oncology and surgical oncology colleagues for their support in times of need. Lastly author would like to thank all the patients who have given consent to be a part of this study and without whom it would not have been possible.