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CLINICAL CASES

Received: September 24^th 2014

Judged: September 25^th 2015

Anthracycline-induced cardiotoxicity: report of fatal cases

Jessica Liliana Vargas-Neri,^a,b,c Osvaldo Daniel Castelán-Martínez,^d María de Jesús Estrada-Loza,^b Yadira Betanzos-Cabrera,^b Rodolfo Rivas-Ruiz^b,e

 

^aDepartamento de Farmacología, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional

^bHospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social

^cHospital Infantil de México Federico Gómez

^dFacultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México

^eCentro de Adiestramiento en Investigación Clínica, División de Investigación en Salud, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social

 

Ciudad de México, México

 

Communication with: Osvaldo Daniel Castelán-Martínez

Email: castelan@unam.mx

 

Background: Anthracyclines are effective drugs in pediatrics cancer treatment. However, anthracycline-induced cardiotoxicity (AIC) is a serious adverse drug reaction that affects the survival in patients treated for childhood cancer.

Clinical cases: Case 1: Nine-year-old girl with stage IV Hodgkin lymphoma with 12 epirubicin doses and a cumulative dose of 576 mg/m². After last chemotherapy dose, the patient was admitted with systemic inflammatory response, asthenia and adinamia. Echocardiography: LVEF of 22 %, SF 11% and moderate mitral regurgitation. Patient died 2 days after diagnosed with dilated cardiomyopathy secondary to anthracyclines. Case 2: Fifteen-year-old girl with stage IV Burkitt lymphoma with two epirubicin doses and a cumulative dose of 90 mg/m². After the last cycle, the patient developed several infectious foci. Echocardiography: LVEF of 49 %, SF 20% and dilated left ventricle with septal flattening. Patient died 13 days after diagnosis of dilated cardiomyopathy by anthracyclines.

Conclusion: AIC is a problem in pediatric patients receiving anthracyclines, monitoring is essential to detect the onset of cardiac damage to provide an intervention to prevent heart failure progress.

Keywords: Chemotherapy; Cardiotoxicity; Heart failure; Anthracycline

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In Mexico, children with cancer have achieved improved survival rates. However, adverse reactions to chemotherapy remain a problem. Anthracyclines are effective chemotherapy drugs for cancer patients¹ and are widely used to treat solid tumors and leukemias, both in children and adults. However, due to its potential cardiotoxic effect, when used in clinical practice, steps must be taken to prevent anthracycline-induced cardiotoxicity (AIC).²

AIC can be divided into early and late. Early cardiotoxicity refers to heart damage that develops during chemotherapy or within the first year of treatment, while late cardiotoxicity is manifested a year or more after finishing treatment with anthracyclines. The risk of heart failure remains for life, especially in children who have a long life expectancy after successful cancer treatment.³

In children, heart damage can be subclinical and reach a prevalence of up to 57%, while the heart failure incidence can reach up to 16% in a period ranging between 0.9 and 4.8 years after treatment.⁴

Some potentially modifiable risk factors have been identified, such as cumulative dose, application rate, concomitant treatments, or physical activity, among others.⁵ It is noteworthy that non-modifiable risk factors include genetic aspects, age, and sex.⁴ Some drugs to prevent the development of cardiotoxicity have also been tested for administration during chemotherapy.⁶ However, the final stage of heart failure is refractory to treatment and heart transplant is the sole therapeutic option. Therefore, monitoring early data of heart disease, especially by echocardiography, is crucial to management with this chemotherapy.⁵

Clinical case 1

A girl nine years three months old, diagnosed with stage IV Hodgkin’s lymphoma on January 31^st, 2013.

The patient presented with fatigue, weakness, pallor, fever, myalgia, and arthralgia. She was evaluated by the oncology department, which performed bone marrow aspirate with normal result, no evidence of infiltration of neoplastic cells. A physical examination revealed pallor of integuments, adequate hydration status, well-hydrated oral mucosa, hyperemic pharynx. No adenomegaly was palpated in the neck. No data of respiratory distress were found, and lung fields had adequate bilateral murmur sounds, and rhythmic heart sounds had good tone and intensity. The abdomen was soft, depressible, with peristalsis present, not painful to surface or deep palpation, with hepatomegaly 4-5-5 cm below the right costal margin, palpable splenic pole at 5-6 cm below the left costal margin. Inguinal adenomegaly on the left side was palpated. Laboratory results on admission were: leukocytes: 36,100/μL, neutrophils: 30,300/μL, Hb: 8.1 g/dL, hematocrit: 27.2%, platelets: 129,000/μL.

Among the initial studies of the patient, she was given echocardiogram prior to initiating chemotherapy. This showed adequate left ventricle ejection fraction (LVEF) (67%) and fractional shortening (FS) of 31%. Chemotherapy received was based on epirubicin (48 mg/m²/dose), bleomycin (10.8 IU/m²/dose), vinblastine (6 mg/m²/dose), and dacarbazine (392 mg/m²/dose) for 12 cycles over 1 year. Treatment ended on February 4th, 2014. The cumulative dose of epirubicin was 576 mg/m². During the subsequent chemotherapy, the outpatient notes described improvement of the patient’s general condition.

Thirteen days after the last chemotherapy cycle, the patient was admitted with data of systemic inflammatory response, intermittent vomiting of food content on multiple occasions, liquid diarrhea (3 stools), hyporexia, asthenia, and adynamia. Due to the severity of the initial signs, the patient was admitted to the pediatric intensive care unit (PICU) on February 17^th, 2014. Twenty-four hours prior to admission, she had begun to have dyspnea and fatigue at medium efforts that, as she told her mother, she had already had starting about eight months earlier.

The patient was evaluated by cardiology. On physical examination, doctors reported that hepatojugular maneuver was performed, which was positive in the chest with hyperdynamic precordium upon auscultation, with presence of third heart sound (s3), second sound with 2p, holosystolic blow I-II grade VI in fourth left intercostal space on midclavicular line.

Echocardiography reported a LVEF of 22%, an FS of 11%, and moderate mitral regurgitation. The report indicated dilated cardiomyopathy and secondary pulmonary hypertension of 40 mmHg. Therefore, management began with dobutamine (10 mcg/kg/min) and noradrenaline (0.1 mcg/kg/min), but due to poor response it was decided to switch to milrinone (0.5 mcg/kg/min) and management started with epinephrine (0.4 mcg/kg/min), which gradually improved metabolic acidosis, so doctors began to decrease the administration of adrenaline and it was suspended on February 18^th, 2014. The patient experienced hypotension again and had to have adrenaline again; she presented increased lactates. Treatment was initiated with levosimendam (0.2 mcg/kg/min). However, on February 19^th, 2014 the patient presented hemodynamic deterioration and presence of sustained hypotension with data of generalized tissue hypoperfusion, oliguria, increased lactate at 7 mg/dL, and electrocardiographic changes with data of endocardial injury. Finally, the patient died the same day, diagnosed with dilated cardiomyopathy secondary to anthracyclines.

Clinical case 2

Female patient fifteen years nine months old, diagnosed on June 6^th, 2014 with non-Hodgkin’s lymphoma, Burkitt type stage IV. Her condition began one month before diagnosis with generalized pallor, unquantified nocturnal fever, and increased volume in the left mandibular region with rapid growth, painless, hard, and not mobile, which limited her mouth opening. On her admission to the oncology department, she was found to have pancytopenia with a blood count with Hb 4.4 g/dL, hematocrit 16.9%, leukocytes 6,800/μL, neutrophils 400/μL, lymphocytes 2,700/μL, and platelets 50,000/μL. Bone marrow aspirate was taken and 20% blasts were found. A transfusion support plan as well as tumor anti-lysis measures were initiated. Chemotherapy was administered on June 6^th, 2014 based on vincristine (1.5 mg/m²/dose), cyclophosphamide (300 mg/m²/dose), epirubicin (45 mg/m²/dose) and intrathecal chemotherapy based on methotrexate, cytarabine, and hydrocortisone.

Twelve days after administration of the first cycle of chemotherapy, the patient was admitted to the emergency department with a pustule in the left inguinal region with erythema, hyperemia, and pain at palpitation; the pustule had spontaneous drainage. It was managed with dicloxacillin and the patient improved. On July 1^st, 2014 the second cycle of chemotherapy was administered based on epirubicin (45 mg/m²/dose, cumulative dose of 90 mg/m²) and vincristine (1.5 mg/m²/dose). On July 7^th, the patient presented with right forearm edema with hyperemia and induration localized at the elbow joint; a pustule of 10 cm and intermittent fever were then added. General malaise and sweating was observed. On July 9^th the presence of dyspnea, data of respiratory deterioration with the presence of severe metabolic acidosis, and hyperlactatemia of 8.5 mg/dL were added. It was decided to do advanced airway management and send the patient to the PICU.

The patient was evaluated by cardiology on July 10^th. Doctors report that she was without cyanosis; there was no precordial activity, no murmurs were auscultated, and the second tone was normal. Echocardiography reported a LVEF of 49% and FS 20%, no septal defects and no significant gradients of outflow tracts or aortas. E-point septum distance was 14.9 mm. The pulmonary artery was permeable with confluent branches. Left ventricle dilation with septal flattening was observed. No thrombi or vegetation were observed. The report indicated dilated cardiomyopathy due to anthracycline.

In the PICU the patient experienced hemodynamic instability, managed with noradrenaline due to septic shock in hyperdynamic phase, and dobutamine and a wide range of antibiotics required according to the results of the isolates, since the patient had pneumonia from Candida fumata and Stenotrophomonas maltophilia, and Aeromonas hydrophila and Acitenobacter baumannii were isolated from the right arm lesion. On July 21^st BMA was performed, which showed a greater blast count, and it was decided to start chemotherapy with vincristine (1.5 mg/m²/dose) and cytarabine (300 mg/m²/dose). After the chemotherapy, cannula and mouth bleeding was observed, with clear data of disseminated intravascular coagulation and renal impairment. The patient presented cardiorespiratory arrest that did not respond to advanced resuscitation maneuvers. She died on July 23^rd, 2014.

Discussion

Anthracyclines have been incorporated in more than 50% of protocols to treat pediatric cancer and, together with other chemotherapies, they have helped to increase five-year survival of children diagnosed with cancer up to 80%.⁷ However, AIC is a serious adverse reaction affecting the survival of children and young cancer survivors long-term.⁸ 

Among cancer survivors, cardiovascular disease is the leading cause of morbidity and mortality, only after recurrence and secondary cancers.⁹ AIC was the cause of death of the patients described in this report and is associated with a progressive and irreversible deterioration of cardiac function that begins asymptomatically and can progress to severe heart failure.^10,11 For our patients, no clinical data of respiratory distress were reported, since heart failure remains subclinical until debuting in the form of heart failure, just when there is little to offer these patients. In these cases, an infection decompensated the patients and only upon evaluation by echocardiogram was the diagnosis of AIC established.

AIC is thus defined as a decreased left ventricle ejection fraction (LVEF) > 5% of a baseline LVEF < 55% with symptoms of heart failure, or asymptomatic reduction of LVEF > 10% of baseline LVEF < 55%.¹² It can manifest with clinical symptoms of heart failure, or may be subclinical with cardiac abnormalities detected only by various diagnostic methods, such as biomarkers and imaging studies. Because subclinical abnormalities can affect up to half of children who receive anthracyclines,¹³ the American Heart Association recommends serial echocardiographic monitoring of pediatric patients during and after treatment with anthracyclines, including Doppler analysis, M-mode echocardiography, two-dimensional transthoracic echocardiography, and, when necessary, transesophageal echocardiography.^7,8 Although this recommendation has been criticized due to the low sensitivity of echocardiography to detect early-stage cardiotoxicity,¹⁰ it becomes useful when echocardiograms are made serially during and after treatment with anthracyclines, as these allow you to visualize trends in ventricular function and thus facilitate the detection of asymptomatic cardiotoxicity to provide timely intervention and prevent the patient getting to congestive heart failure.

The mechanisms involved in the cardiotoxic effects have not been fully elucidated, but lipid peroxidation, the generation of free radicals by iron-anthracycline complexes, and cardiolipin-anthracycline complex formation play a significant role.¹⁴

AIC has been described as dose-dependent, but that is not the only factor that determines its appearance. In case 1, the patient had AIC shortly after finishing chemotherapy with high doses of anthracycline. The patient arrived at the hospital when little could be done, because AIC is refractory to treatment. Currently, treatment protocols used in pediatric patients limit anthracycline exposure to 450-550 mg/m². This cumulative dose (CD) corresponds to a 5% incidence of clinical cardiotoxicity.¹⁵ However, the role of cumulative doses is unclear, as there are described cases of 240 mg/m².¹⁶ This is evident in case 2, in which the cumulative dose was 90 mg/m². Therefore, although high cumulative doses are major risk factor for the development of AIC, they are not the only factor. Drafts et al. showed that low and moderate doses (50-375 mg/m²) of anthracyclines are associated with the early development of AIC.¹⁷ Furthermore, Stoodley et al. found that there are alterations in diastolic ventricular function immediately after administration of anthracyclines at low doses.¹⁸ One explanation of the interindividual variability for the development of AIC at different doses is the presence of genetic variants that increase some patients’ susceptibility to have this when they receive anthracyclines. For this reason, it can be concluded that there is no "safe" dose, so monitoring of ventricular function is recommended in all patients receiving anthracyclines. 

Therefore monitoring by echocardiogram is recommended during and after treatment. This is the only move that could slow the development of AIC, as it allows timely identification of patients and, in some cases, the starting point to begin treatment.

Other risk factors for developing cardiotoxicity have been described, which include, as in the case of our patients, female gender (it is reported that girls have about twice the risk of cardiotoxicity as boys), age at cancer diagnosis (with a 16.7% higher prevalence in children under 4 years), time elapsed after the end of chemotherapy (5 to 9 years), the presence of preexisting cardiac risk factors (hypertension, heart morbidities, previous cardiotoxic treatments), underweight, African-American ancestry, concomitant chest radiotherapy (more than 30 to 5 Gy cumulative radiation to the heart), concomitant treatment with chemotherapy drugs (cyclophosphamide, bleomycin, vincristine, amsacrine, etc.), and comorbidities (obesity, kidney dysfunction, pulmonary disease, etc.).^3,7 

In addition to monitoring and decreasing doses of anthracyclines, various strategies have been tried to prevent or reduce AIC. These include developing less cardiotoxic anthracycline analogs, such as idarubicin, using liposomal anthracyclines, reducing the accumulated dose, and using different cardioprotective agents such as dexrazoxane.^3,19 In this regard, dexrazoxane has been shown to reduce heart damage induced by anthracyclines (RR 0.29, with 95% CI of 0.20 to 0.41). This evidence suggests their use to prevent AIC.²⁰ Dexrazoxane should be administered 30 minutes before the administration of any anthracycline. However, despite these efforts, AIC remains a problem among pediatric patients receiving anthracyclines, so monitoring during and after chemotherapy is essential to identify children who begin to have heart damage and, thus, to provide them with a timely intervention to prevent them developing heart failure.

Acknowledgment

Jessica Liliana Vargas-Neri thanks CONACyT for grant number 289171 and IMSS for tuition scholarship 99096774.

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