Cancer has been reported as a main reason behind mortality over the world in all age groups including the pediatric population. Approximately 9.6 million people die from various cancers worldwide annually. Surgical excision of tumor, radiation treatment and administration of chemotherapy drugs are important tools in management of the disease. Despite therapeutic benefits of chemotherapy, there are adverse effects of various chemotherapy drugs. According to reports, 7.25–27 percent of cardiovascular deaths in cancer patients are caused by chemotherapy-induced cardiotoxicity (1).

Anthracyclines are one of the highly effective anticancer medications categories, which include doxorubicin. A mutant strain of Streptomyces peucetius led to the discovery of doxorubicin, an anthracycline antibiotic. Doxorubicin modulate several cellular pathways, such as iron metabolism, disruption of calcium balance, modification of enzyme activity, and topoisomerases mediated DNA damage (2). A naphthacenequinone nucleus and the amino sugar daunosamine make up the compound doxorubicin. Doxorubicin can attach to cell membranes and plasma proteins because it possesses hydrophilic and hydrophobic areas. Additionally amphoteric, doxorubicin serves both acidic and basic purposes. It made it feasible for doxorubicin to cross the cellular compartments. Intracellularly, doxorubicin can be converted to doxorubicinol, a metabolite with biological action  (3).

The incidence of cardiac dysfunction has been shown to rise over time with the use of anthracycline-based chemotherapy (4). A poor prognosis and a high fatality rate have been linked to severe cardiotoxicity. Early therapeutic intervention for cardiac decompensation may be made possible by early diagnosis of cardiac toxicity. For ongoing heart performance monitoring, several facilities have used echocardiography (5). Electrocardiograms show non-specific ST-T wave abnormalities in acute cardiotoxicity, which manifests during therapy or shortly after, as aberrant heartbeat changes. Up to 40% of individuals who receive doxorubicin have reported experiencing acute bouts. Acute episodes have not been found to be a reliable indicator of late-onset heart dysfunction (6).

Our centre provides tertiary level diagnostic and therapeutic services for children with cancer in Uttarakhand and its neighbouring states. Children with cancers such as Leukemia, Lymphomas-Hodgkin and Non-Hodgkin, Brain tumors, Wilms tumor, Neuroblastoma, Retinoblastoma, Bone tumor - Osteosarcoma and Ewings sarcoma etc are being treated here. Doxorubicin is an integral part of the chemotherapy protocol in most of these conditions. Therefore, this study has been planned with the aim of studying doxorubicin induced cardiac dysfunction in children with cancer.

Study design: Present study was prospective, observational, single centric, hospital-based study conducted at the department of pediatrics at host institute. Total 53 children who have received Doxorubicin over a period of 1 year (minimum 40) were included in the study. Children with a congenital and acquired heart disease or receiving any other cardiotoxic medication were exclude from the study.

Assessment of cardiac function: Cardiac functions were assessed by two-dimensional, M-mode, and Doppler Echocardiography. Echocardiograms was done in all the patients who were given doxorubicin and other chemotherapeutic agents for various malignancies. Left ventricular performance was assessed by a baseline 2 D Echocardiography before the start of doxorubicin i.e., before the first dose, prior to each subsequent dose, and every two to three months following the last dose of doxorubicin. Abnormal Echocardiography findings depicted the changes that occurred because of the last given dose of Doxorubicin.

Statistical analysis: The statistical analysis was carried out using SPSS 27.0. For quantitative variables, mean and standard deviation was used as measures of central tendency and variability respectively. For qualitative variable, fraction of total and percentages was calculated. Chi-square test was used to compare two qualitative groups and unpaired t-test was used to compare two quantitative groups. A p value <0.05 was considered as significant.

The mean age of all patients included in our study was 8.792 ± 4.796 years. Mean age of patients who received the cumulative dose of doxorubicin (CDD) below 200 mg/m² was 10.83 ± 5.269 years and of those who received the CDD ≥200-300 mg/m² was 8.532 ± 4.730 years. There were 38 (71.69%) male patients and 15 (28.30%) female patients. In patients who received the CDD <200 mg/m², there were 3 males and 3 females. In patients who received the CDD ≥200-300 mg/m², there were 35 males and 12 females (Table 1).

LVEF was >50% in 49 patients whereas 4 patients have the LVEF<50%. In patients who received the CDD <200 mg/m², LVEF was >50% in 5 patients whereas 1 patient have the LVEF<50% and of those who received the CDD ≥200-300 mg/m², LVEF was >50% in 44 patients whereas 3 patients have the LVEF<50% (Table 2).

In patients having normal LVEF≥50%, the LVEF was found to be decreased by 1 to 4 points after starting of doxorubicin therapy but was within normal limits (Table 3).

Among total 4 patients who have the LVEF<50%, the LVEF was found to decreased by 2 to 8 points (Table 4).

At follow up of three to six months, among total 4 patients who have the LVEF<50%, the LVEF was found to increase by 1 to 3 points (Table 5).

With elevated chances of cardiac dysfunction at 300 mg/m2 doxorubicin, it has been frequently recognised as a limiting factor in the treatment of malignancies. This study examined the prevalence of doxorubicin cardiac dysfunction children with cancer in a setting with limited resources. In this paediatric cohort, one patient has the LVEF<50% among patients who receive the CDD <200 mg/m² whereas there were 3 patients who receive the CDD ≥200 mg/m² have LVEF<50%.

Our results are in agreement with other research looking for doxorubicin cardiotoxic effects. Migrino et al. investigated the cardiotoxicity in rats brought on by doxorubicin. They found that data obtained from 2-D ECHO was helpful in the early diagnosis of doxorubicin induced cardiac dysfunction (7). Tsai et al. used 2D-STE to examine the long-term impact of doxorubicin on LV systolic performance. They discovered that patients receiving doxorubicin together with mediastinal radiation had lower overall longitudinal strains than patients getting radiotherapy without anthracyclines (8). Piegari et al. reported similar findings, demonstrating that strain rate imaging is highly effective in recognising early cardiac alterations brought on by doxorubicin therapy compared to the traditional ECHO parameters (9). After two and four weeks of therapy, the echocardiogram was performed. The limitations of the research by Migrino et al. and Piegari et al., however, were that they were conducted using animal models, thus their results cannot be generalised to humans, but they may be used as a guide.

In our study, patients who received the doxorubicin cumulative dose <200 mg/m² found to have low cardiotoxicity compared to patients who received the doxorubicin cumulative dose 200-300 mg/m². Similarly, Radu et al. discovered that a low dosage doxorubicin regimen in children is associated with a reduction in LVEF (10). In the study by According to Mohta et al., out of 24 children, patients receiving doxorubicin had cardiotoxity in 26% of cases and daunorubicin in 33% of cases. Their mean EF ranged from 37.5 to 52.6 percent, with a mean of 44.6 percent. Only 14.28 percent of patients had palpitations and exertional dyspnea, which are symptoms related to the cardiovascular system. None of these patients needed medication therapy for cardiac dysfunction or had congestive HF (11).

One of the advantages of present study is that we perform the follow up of patients for the improvement in cardiac function over the period of six months. It was found from the LVEF data that cardiac function improves after cessation of doxorubicin. Similar results were observed in the study by Moyo et al. in which no deterioration of systolic function was found among 20 children who completed follow-up (10).

As a disadvantage, the present study lacks the comparison of the 2D longitudinal strain echocardiography with considerably more antiquated tools for evaluating heart function. The gold standard for determining LV deformation, cardiac magnetic resonance, which is not compared to the 2D longitudinal strain echocardiography in this study. Additionally, the patients took a variety of additional medications during the trial. Therefore, it is uncertain if doxorubicin or other cytotoxic medications are to blame for the cardiotoxic consequences. We were unable to exclude a subset of patients from receiving doxorubicin therapy in order to include them as a control group due to ethical concerns. The fact that the echocardiograms were not read without any bias is another drawback of the study.

Despite the limitations mentioned above, the current investigation has demonstrated instances of asymptomatic LVEF reduction among kids who had chemotherapy regimens containing doxorubicin in our environment. To comprehend the real scope of these early asymptomatic alterations in heart function and their implications on the long-term treatment outcome, bigger investigations need to be conducted, this will serve to guide cardiac safety monitoring and optimise doxorubicin dose for the treatment of paediatric cancers.

Cardiotoxicity during and after chemotherapy, particularly in children, is a problem that is becoming more and more common, exposing more and more cancer survivors to the danger of HF. Priority should be given to comprehending the mechanisms causing irreversible heart malfunction and quickly identifying therapy targets. In this present study, one patient who received the CDD <200 mg/m² and three patients who received the CDD ≥200 mg/m² was found to have cardiotoxicity indicated by LVEF<50%. After starting doxorubicin therapy, LVEF was found to decline within four-point range. Also, after cessation of doxorubicin 2 D ECHO at follow up of three and six months was done that showed decreased cardiotoxicity, the LVEF was found to be increased by 1 to 3 points. Cardiac function assessment needs to be analyzed critically in children undergoing chemotherapy to improve prognosis

1. Shah SC, Kayamba V, Peek Jr RM, Heimburger D. Cancer control in low-and middle-income countries: is it time to consider screening? Journal of global oncology. 2019;5:1-8.
2. Mitry MA, Edwards JG. Doxorubicin induced heart failure: Phenotype and molecular mechanisms. International journal of cardiology. Heart & vasculature. 2016;10:17-24.