Cardiac Late Effects and Prevention Strategies for Children Treated with Anthracyclines

Size: px

Start display at page:

Download "Cardiac Late Effects and Prevention Strategies for Children Treated with Anthracyclines"

Arthur Smith
6 years ago
Views:

1 Cardiac Late Effects and Prevention Strategies for Children Treated with Anthracyclines a report by Dr Andrea S Hinkle, 1,2 Cindy B Proukou, 2,3 Sampada S Deshpande, 1 Sarah A Duffy, 1 Amy M Kozlowski, 1 Carol A French, 1,2 and Dr Steven E Lipshultz 1,2 1. Division of Pediatric Cardiology, Golisano Children s Hospital at Strong and University of Rochester Medical Center; 2. Department of Pediatrics, University of Rochester School of Medicine and Dentistry; and 3. Division of Hematology/Oncology, Golisano Children s Hospital at Strong and University of Rochester Medical Center, Rochester, New York Cardiotoxicity is a well-recognised late effect of therapy for childhood and adolescent malignancies and is a serious problem for long-term survivors. Cardiotoxicity may be caused by chemotherapy, radiation therapy or the combined use of both modalities. A survey of paediatric cardiology centres in North America found that more than 12% of all patients with cardiomyopathy had been treated for cancer during childhood or adolescence. 1 In a large cohort of American patients who had survived at least five years from a diagnosis of paediatric cancer, the standardised mortality ratio (SMR) for overall mortality was 10.8 and the SMR for cardiac mortality was A study from the Nordic countries produced similar findings (overall SMR, 10.8; cardiac and circulatory system death SMR, 5.8). 3 The SMR for sudden or ill-defined deaths was 3.9; some of these deaths were probably attributable to cardiac causes. Mortality from anthracycline-induced cardiac failure is substantial, with some large studies reporting rates higher than 20%. 4,5 A study of year survivors of childhood cancer found overall SMRs of 3.78 for men and 4.84 for women, with a cardiac SMR for men of Exposure to doxorubicin was associated with higher risk of death from cardiac disease. Cardiotoxicity can present as acute, early onset or late onset. It may be subclinical and asymptomatic or progressive with the development of clinical symptoms. Clinical presentation and relationship to known risk factors for chemotherapy-induced cardiotoxicity differ, particularly between acute cardiotoxicity and other categories. 7 Acute cardiotoxicity may occur with or without subsequent development of other forms of cardiotoxicity. Early-onset cardiotoxicity occurs during therapy or within the first year after treatment, and is defined as congestive heart failure not attributable to other known causes or changes in cardiac function that prompted permanent discontinuation of anthracycline therapy. 8 Late toxicity occurs at least one year after the completion of therapy and is defined by an abnormal end systolic wall stress (afterload) or contractility. 9 Of a cohort of 6,493 childhood cancer patients treated with anthracycline, 1.6% were reported to have developed early clinical cardiotoxicity. 8 Late-onset cardiotoxicity 1. S E Lipshultz, Ventricular Dysfunction Clinical Research in Infants, Children and Adolescents, Progress in Pediatric Cardiology, (2000), pp A C Mertens, Y Yasui, J P Neglia, et al., Late Mortality Experience in Five-year Survivors of Childhood and Adolescent Cancer: The Childhood Cancer Survivor Study, Journal of Clinical Oncology, 19 (2001) 13, pp. 3,163 3, T R Moller, S Garwicz, L Barlow, et al., Decreasing Late Mortality Among Five-year Survivors of Cancer in Childhood and Adolescence: A Population-based Study in the Nordic Countries, ibid., pp. 3,173 3, D D Von Hoff, M W Layard, P Basa, et al., Risk Factors for Doxorubicin-induced Congestive Heart Failure, Annals of Internal Medicine, (1979), pp. 97,710 97, C Praga, G Beretta, P L Vigo, et al., Adriamycin Cardiotoxicity Survey of 1273 Patients, Cancer Treatment Reports, 63 (1979) 5, pp D M Green, A Hyland, C S Chung, et al., Cancer and Cardiac Mortality Among 15-year Survivors of Cancer Diagnosed During Childhood or Adolescence, Journal of Clinical Oncology, 17 (1999) 10, pp. 3,207 3, A Giantris, L Abdurrahman, A Hinkle, et al., Anthracycline-induced Cardiotoxicity in Children and Young Adults, Critical Reviews in Oncology/Hematology, 27 (1998) 1, pp J P Krischer, S Epstein, D D Cuthbertson, et al., Clinical Cardiotoxicity Following Anthracycline Treatment for Childhood Cancer: The Pediatric Oncology Group Experience, Journal of Clinical Oncology, 15 (1997) 4, pp. 1,544 1, S E Lipshultz, S D Colan, R D Gelber, et al., Late Cardiac Effects of Doxorubicin Therapy for Acute Lymphoblastic- Leukemia in Childhood, New England Journal of Medicine, 324 (1991) 12, pp

2 2 is also described in more than half of a cohort of 115 children treated for acute lymphoblastic leukaemia (ALL) with doxorubicin from one to 15 years earlier. 9 Anthracyclines are the most common class of chemotherapeutic agents associated with adverse effects on the heart. Anthracyclines were introduced as chemotherapeutic agents in the late 1960s (daunorubicin) and early 1970s (doxorubicin). 10 They are highly effective against a wide range of malignancies, and survival from paediatric cancers has increased from 45% to 77% since their introduction, although some of the improvement can be attributed to other agents and improvements in supportive care. 11 Thus, the benefits of anthracyclines currently outweigh their cardio-toxicity. The most commonly used drugs in this class are doxorubicin (Adriamycin), daunorubicin (Cerubidine) and idarubicin (Idamycin). 7 Other chemotherapeutic agents that may cause cardiac abnormalities include alkylating agents, antimetabolites and antimicrotubule agents (see Table 1). 12,13 Some factors that influence the development of cardiotoxicity can be modified to decrease patient risk. These factors include the type of anthracycline, the cumulative dose of anthracycline, the rate of administration, the use of cardioprotectants and concomitant mantle radiation. 7 Higher cumulative doses were associated significantly with the development of cardiotoxicity on the Pediatric Oncology Group (POG) protocols from 1974 to The risk of cardiotoxicity in children treated with 550mg/m 2 or more was five times higher than the risk in children treated with lower cumulative doses. In fact, a high cumulative dose of anthracycline was the strongest predictor of cardiotoxicity. It was recently reported that serum measurements of cardiac troponin-t (ctnt) were elevated in children who received doxorubicin for ALL by either a continuous or bolus infusion, suggesting that the lower-peak doxorubicin concentrations in continuous infusions failed to prevent cardiac damage. 14 It was also recently reported that, in a randomised prospective multi-centred study of dexrazoxane in newly diagnosed childhood ALL patients treated with doxorubicin, there is a 50% reduction in cardiac troponin, indicating significant reduced acute myocardial injury during therapy and no difference in event-free survival or toxicities at two to three years of follow-up. 15 Another approach to minimising chemotherapyinduced cardiotoxicity would be to combine antineoplastic therapy with agents that reduce oxidative stress, such as probucol, 7 vitamin E, glutathione, amifostine and mesna. These agents may offer promise in reducing or preventing cardiomyopathy but the mechanism that protects against oxidative stress injury may also limit antineoplastic efficacy. 12 Although widely accepted that the concomitant exposure of the mantle (mediastinum) to radiation and anthracycline enhances the risk of cardiotoxicity, the evidence is suggestive rather than conclusive. 7 Another emerging approach to reducing cardiomyopathy is to replace conventional anthracyclines with less cardiotoxic analogues or new formulations, such as epirubicin hydrochloride, idarubicin hydrochloride and liposomal anthracyclines. 12 Other factors that affect the potential for the development of cardiomyopathy cannot be altered. These factors include such patient characteristics as age at time of treatment, gender, race and length of follow-up. Additional patient characteristics that may influence the development of cardiomyopathy include pre-existing or concomitant medical conditions and treatments. A retrospective study of children and adults who had received cumulative doxorubicin doses of 244mg/m 2 to 550mg/m 2 for ALL or osteosarcoma during childhood showed that younger age at diagnosis was associated with, and predictive of, ventricular dysfunction. 16 It was found that female patients were more likely to have depressed contractility than male patients. 16 Of the cohort of 120 children and adults that had been treated with bolus doxorubicin with cumulative doses of at least 244mg/m 2 for ALL (73%) or nonmetastatic osteogenic sarcoma (27%), 45% of the female patients (28 of 62) had contractility more than two standard deviations below normal, compared with 12% of male patients (seven of 58; p<0.001). In addition, the higher the cumulative dose, the greater the difference in contractility between male and female patients. In a review of children treated on POG protocols between 1974 and 1990, African-American children and children with trisomy 21 (without congenital cardiovascular malformations) were both associated with a higher risk of early cardiotoxicity. 8 It has been shown that asymptomatic cancer survivors are at increasing risk for cardiac dysfunction later in life. Sixty-five per cent of childhood cancer survivors treated with anthracyclines have subclinical cardiac dysfunction six years after completion of therapy and the dysfunction is often progressive. 7,9,16,17 Heart failure may develop after an added stress on the heart, such as pregnancy, infection, an unsupervised exercise programme or cocaine use. Monitoring cardiac function is thus extremely important during pregnancy or other events that can increase stress on the heart. 18 Advances in chemotherapy have significantly increased the number of children cured of childhood cancer. However, the toxicities associated with chemotherapy affect the quality of the cure. Curing childhood cancers

3 Cardiac Late Effects and Prevention Strategies for Children Treated with Anthracyclines remains the priority, but measures can be taken to minimise the development of cardiotoxicity. Treatment protocols should be adjusted on the basis of knowledge about cardiotoxicity, which is affected by cumulative dose, dosing regimens, concomitant therapy and strategies to reduce cardiotoxicity (dose adjustments, use of cardioprotectants and use of less cardiotoxic analogues). Long-term cancer survivors require continual monitoring. Patients with early evidence of cardiac damage are at greatest risk for cardiomyopathy, but many patients may also develop late cardiotoxicity. Predicting individual risk for the development and progression of cardiotoxicity is difficult. Continuing study is needed to further refine detection and monitoring strategies. Echocardiography is a widely available, non-invasive test appropriate for children, and advances in this technology have allowed the detection of subclinical changes. Laboratory tests, particularly for cardiac troponins, such as ctnt and cardiac troponin-i (ctni) also show promise in identifying patients at higher risk. In a prospective study of 202 children with newly diagnosed ALL, about 35% had ctnt elevations during doxorubicin therapy. 19 The ctnt elevations were significantly more frequent in patients who received cumulative doxorubicin doses of more than 60mg/m 2 than in patients who received less than 60mg/m 2. Higher dose was also associated with chronically elevated ctnt for a period of five months. Other laboratory tests examined that have potential usefulness in detecting anthracycline-induced damage include atrial natriuretic peptides (ANPs) and brain natriuretic peptides (BNPs). In one study in children, both BNPs and ANPs were significantly elevated in children with echocardiographic evidence of left ventricular dysfunction and the elevations were associated with systolic function but not diastolic function. 20 Radiologic techniques that detect the biochemical changes in cardiac injury may allow more sophisticated imaging and detection of permanent and potentially progressive heart damage. Exercise radionuclide angiography has excellent sensitivity and specificity for detecting coronary disease, but its application to detecting anthracycline cardiomyopathy is not adequately studied. 21 Several other imaging modalities have been explored for monitoring anthracycline toxicity but remain investigational. These include Indium-111 antimyosin scintigraphy for the detection of myocardial cell injury, and iodine-123 meta-iodobenzylguanidine scintigraphy to assess cardiac adrenergic innervation, which is disrupted by anthracycline toxicity. 10,22 24 A study of iodine-123 beta-methyl-iodophenylpentadecanoic acid dynamic single photon emission computed tomography detected early evidence of doxorubicin cardiomyopathy. Magnetic resonance spectroscopy and positron emission tomography scanning are also being investigated to evaluate anthracycline cardiac damage. 25,26 These imaging modalities have been studied in animals and adults, but data on children is not available. The goal of each of these assessments is to identify patients at risk and allow appropriate monitoring schedules and necessary interventions. Patients with subclinical monitoring abnormalities should be referred to a cardiologist for intervention and subsequent follow-up testing. Current treatment for subclinical chemotherapy-induced cardiomyopathy focuses on correcting the underlying abnormalities, such as increased afterload and decreased contractility. 27 There is no specific therapy for chemotherapy-related cardiomyopathy, and thus treatment is guided by the type of cardiomyopathy (dilated, restrictive, etc.). 10. L J Steinherz and L H Wexler, The Prevention of Anthracycline Cardiomyopathy, Progress in Pediatric Cardiology, 8 (1998) 3, pp A Jemal, A Thomas, T Murray, et al., Cancer Statistics 2002, Cancer, 52 (2002) 1, pp V C Simbre, M J Adams, S S Deshpande, et al., Cardiomyopathy Caused by Antineoplastic Therapies, Current Treatment Options in Cardiovascular Medicine, (2001), pp. 3,493 3, V B Pai and M C Nahata, Cardiotoxicity of Chemotherapeutic Agents, Drug Safety, 22 (2000) 4, pp S E Lipshultz, A L Giantris, S R Lipsitz, et al., Doxorubicin Administration by Continuous Infusion is Not Cardioprotective: The Dana-Farber Acute Lymphoblastic Leukemia Protocol, Journal of Clinical Oncology, 20 (2002) 6, pp. 1,677 1, S E Lipshultz, S D Colan, L B Silverman, et al., Dexrazoxane Reduces Incidence of Doxorubicin-associated Acute Myocardiocyte Injury in Patients with Acute Lymphoblastic Leukemia (ALL), Proc. ASCO, (2002), p. 21,390a. 16. S E Lipshultz, S R Lipsitz, S M Mone, et al., Female Sex and Higher Drug Dose as Risk-Factors for Late Cardiotoxic Effects of Doxorubicin Therapy for Childhood-Cancer, New England Journal of Medicine, 332 (1995) 26, pp. 1,738 1, M A Grenier and S E Lipshultz, Epidemiology of Anthracycline Cardiotoxicity in Children and Adults, Seminars in Oncology, 25 (1998) 4, pp S E Lipshultz, S P Sanders, A M Goorin, et al., Monitoring for Anthracycline Cardiotoxicity, Pediatrics, 93 (1994) 3, pp

4 Table 1: Drugs Associated with Cardiotoxicity Drug Risk Factors Manifestations of Manifestations of Acute Toxicity Chronic Toxicity Cytostatic antibiotics Doxorubicin, Daunoribicin Cumulative dose, rate and schedule of Acute or subacute ECG changes, sinus tachycardia, Early and late onset anthracycline administration, age, mediastinal arrhythmias, pericarditis/myocarditis, MI, sudden cardiac chronic CHF, radiation therapy, female gender, history death, CHF, cardiomyopathy cardiomyopathy of cardiac disorders Epirubicin Unknown CHF CHF Idarubicin Unknown CHF, arrhythmias, angina, MI Mitoxantrone Cumulative doses, prior anthracycline therapy, Arrhythmias, CHF, MI, ECG changes, decreases in LVEF pre-existing cardiovascular disorders Alkylating agents Cyclophosphamide Total dose/cycle or daily dose, prior CHF, chest pain, pleural and pericardial effusions, pericardial anthracycline or mitoxantrone therapy, friction rub, cardiomegaly, loss of QRS voltage on ECG, mediastinal radiation haemorrhagic cardiac necrosis, reversible systolic dysfunction, ECG changes Ifosfamide Total dose CHF, pleural effusion, re-entrant ventricular tachycardia, pulseless tachycardia, ST- or T-wave abnormalities, decreased QRS complex, arrhythmias Cisplatin Unknown Palpitations, left-sided chest pain, nausea, vomiting, dyspnea, hypotension, arrhythmias, interventricular block, MI, STsegment/T-wave changes, T-wave inversions, Raynaud s phenomenon Mitomycin Cumulative dose, prior doxorubicin CHF CHF therapy, chest irradiation Carmustine Unknown Chest pain, hypotension, sinus tachycardia, ECG changes Busulfan Unknown CHF, palpitations, cardiac tamponade, pulmonary congestion, cardiomegaly, pericardial effusion, ECG changes, endocardial/pulmonary fibrosis, pulmonary hypertension Chlormethine Unknown Persistent tachycardia, pulse irregularity, junctional or atria ectopic beats Antimetabolites Fluorouracil History of cardiovascular disorders, prior Angina, MI, hypotension, cardiogenic shock/sudden death, mediastinal radiation, concurrent use of ECG changes, dilated cardiomyopathy other cardiotoxic chemotherapy, rate of administration, higher dose Cytarabine Definitive information unknown, possibly Pericarditis with dyspnea, chest pain, pericardial friction rub, cytarabine dose pulsus paradoxus, CHF, pleural/pericardial effusions, arrhythmias Antimicrotubule agents Paclitaxel Definitive information unknown, possibly Sinus bradycardia/bradyarrhythmias, atrial and ventricular history of cardiovascular disorders arrhythmias, MI, supraventricular tachycardia, AV or leftbundle branch block, sudden death, myocardial dysfunction Etoposide Definitive information unknown, possibly Hypotension, acute MI, ECG changes history of cardiac disease, mediastinal radiation, prior cardiotoxic chemotherapy Teniposide Unknown Arrhythmia, hypotension Vinblastine Acute MI, dyspnea, tachypnea, pulmonary oedema, ECG changes, T-wave inversion, ST segment changes, atrial fibrillation, Raynaud s phenomenon Vincristine Mediastinal radiation, coexisting ischemic Acute MI, dyspnea, tachypnea, pulmonary oedema, ECG heart disease changes, T-wave inversion, ST-segment changes, atrial fibrillation, acute CHF, hypotension, cardiovascular autonomic neuropathy Miscellaneous Amasacrine Hypokalaemia, prior anthracycline therapy Atrial and ventricular tachyarrythmias, CHF, Cardiomyopathy hypotension, cardiopulmonary arrest

5 Cardiac Late Effects and Prevention Strategies for Children Treated with Anthracyclines Cladribine Unknown CHF Asparaginase Unknown Acute MI, ECG changes Tretinoin Unknown Retinoic acid syndrome (fever, respiratory distress, body weight gain, peripheral oedema, pleural-pericardial effusions), MI Pentostatin Definite information unknown, possibly Angina and MI, CHF, acute arrhythmias CHF underlying cardiovascular disorders Trastuzumab Prior or concomitant anthracycline use Ventricular dysfunction, CHF Cardiomyopathy Arsenic trioxide Unknown Arrhythmias, pericardial effusion Interferon alpha-2a Unknown Exacerbation of underlying cardiac disease, hypotension, Cardiomyopathy arrhythmias Interleukin-2 Unknown Myocardia injury/myopericarditis, ventricular arrhythmias Dilated hypotension, sudden death cardiomyopathy Key: AV = atrioventricular; CHF = congestive heart failure; ECG = electrocardiogram; LVEF = left ventricular ejection fraction; MI = myocardial infarction. Therapy with angiotensin-converting enzyme inhibitors and/or beta-blockers may delay subclinical abnormalities from deteriorating to symptomatic heart failure. 12 One study with the use of betablockers has shown that the left ventricular ejection fraction of patients with doxorubicin-induced cardiomyopathy improved from 28% to 41% after treatment. 28 The mechanism by which beta-blockers improve myocardial function may include reducing oxidative stress and the rate of apoptosis. 12 Afterload reduction with enalapril may alter the course of progressive ventricular dysfunction for patients with or without heart failure. In a randomised study, captopril was given to patients with some systolic dysfunction but without severe left ventricular dilatation. Overall mortality in the captopril group was 19% lower than in the placebo group. 29 Further study and follow-up will define which evaluations are most useful. There have been many advances in the area of paediatric oncology, but further investigation is needed to eliminate the cost of the cure. A version of this article containing an additional table of information can be found in the Reference Section of the CD-ROM accompanying this business briefing. 19. S E Lipshultz, S E Sallan, V Dalton, et al., Elevated Serum Cardiac Troponin-T as a Marker for Active Cardiac Injury During Therapy for Childhood Acute Lymphoblastic Leukemia (ALL), Proc. ASCO, (1999), p. 18,568a. 20. F Hayakawa, Y Komada, M Hirayama, et al., Plasma Levels of Natriuretic Peptides in Relation to Doxorubicin-induced Cardiotoxicity and Cardiac Function in Children with Cancer, Medical and Pediatric Oncology, 37 (2001) 1, pp L J Steinherz, T Graham, R Hurwitz, et al., Guidelines for Cardiac Monitoring of Children During and After Anthracycline Therapy Report of the Cardiology Committee of the Childrens-Cancer-Study-Group, Pediatrics, 89 (1992) 5, pp L C M Kremer, E C van Dalen, M Offringa, et al., Anthracycline-induced Clinical Heart Failure in a Cohort of 607 Children: Long-term Follow-up Study, Journal of Clinical Oncology, 19 (2001) 1, pp T Nousiainen, E Vanninen, E Jantunen, et al., Anthracycline-induced Cardiomyopathy: Long-term Effects on Myocardial Cell Integrity, Cardiac Adrenergic Innervation and Fatty Acid Uptake, Clinical Physiology, 21 (2001) 1, pp T J Jeon, J D Lee, J W Ha, et al., Evaluation of Cardiac Adrenergic Neuronal Damage in Rats with Doxorubicininduced Cardiomyopathy Using Iodine-131 MIBG Autoradiography and PGP 9.5 Immunohistochemistry, European Journal of Nuclear Medicine, 27 (2000) 6, pp P Nony, J P Guastalla, P Rebattu, et al., In Vivo Measurement of Myocardial Oxidative Metabolism and Blood Flow does not Show Changes in Cancer Patients Undergoing Doxorubicin Therapy, Cancer Chemotherapy and Pharmacology, 45 (2000) 5, pp S Schaefer, Magnetic Resonance Spectroscopy in Human Cardiomyopathies, Journal of Cardiovascular Magnetic Resonance, 2 (2000) 2, pp K Nysom, K Holm, S R Lipsitz, et al., Relationship Between Cumulative Anthracycline Dose and Late Cardiotoxicity in Childhood Acute Lymphoblastic Leukemia, Journal of Clinical Oncology, 16 (1998) 2, pp S E Lipshultz, Dexrazoxane for Protection Against Cardiotoxic Effects of Anthracyclines in Children, Journal of Clinical Oncology, 14 (1996) 2, pp M A Pfeffer, E Braunwald, L A Moye, et al., Effect of Captopril on Mortality and Morbidity in Patients with Leftventricular Dysfunction After Myocardial Infarction Results of the Survival and Ventricular Enlargement Trial, New England Journal of Medicine, 327 (1992) 10, pp

Vasospasm and cardiac ischemia (Type 3 ) Hypertension Hypotension Arrhythmias Miscellaneous ( pericardial inflammation, valvular abnormalities )

Management of Cardiotoxicity due to Systemic Cancer Therapy Left Ventricular Dysfunction Type 1 cardiac dysfunction Type 2 cardiac dysfunction Vasospasm and cardiac ischemia (Type 3 ) Hypertension Hypotension