cardiovascular-agents and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

To evaluate the technologies used to reduce anthracycline-induced cardiotoxicity in children. Also to evaluate cardiac markers to quantify cardiotoxicity, and identify cost-effectiveness studies and future research priorities.. Eight electronic databases were searched from inception to January 2006. Bibliographies of related papers were assessed for relevant studies and experts contacted to identify additional published references.. A systematic review of the evidence was undertaken using a priori methods.. Four randomised controlled trials (RCTs) met the inclusion criteria of the review, each considering a different cardioprotective intervention; all trials included children with acute lymphoblastic leukaemia, and one also included children with non-Hodgkin's lymphoma. However, all had methodological limitations. No cost-effectiveness studies were identified. One RCT and six cohort studies on the use of cardiac markers met the inclusion criteria of the review, but also had methodological limitations. Of the two RCTs that considered continuous infusion versus bolus (rapid) infusion, one found that continuous infusion of doxorubicin did not offer any cardioprotection over bolus; the other suggested that continuous infusion of daunorubicin had less cardiotoxicity than bolus. Two studies considered cardioprotective agents, one concluded that dexrazoxane prevents or reduces cardiac injury without compromising the antileukaemic efficacy of doxorubicin and the other reported a protective effect of coenzyme Q10 on cardiac function during anthracycline therapy. One RCT suggested that cardiac troponin T can be used to assess the effectiveness of the cardioprotective agent dexrazoxane. Two cohort studies considering atrial natriuretic peptide and two considering brain (B-type) natriuretic peptide suggested that these chemicals are elevated in some subgroups of children treated with anthracyclines for cancer. N-terminal B-type natriuretic peptide levels were significantly elevated in children treated with anthracyclines who had cardiac dysfunction. One cohort study found that serum lipid peroxide was higher in younger children treated with doxorubicin than correspondingly aged children not receiving doxorubicin. No differences in carnitine levels were found in children treated with doxorubicin and a group of healthy children in one cohort study.. It is difficult to draw conclusions about the effectiveness of technologies for reducing or preventing cardiotoxicity and about the use of cardiac markers in children as the evidence is limited in quantity and quality. The lack of standardisation for monitoring and reporting cardiac performance is problematic. Not all studies report effectiveness in terms of cardiac outcomes and event-free survival with supporting statistical analyses. Studies are mostly small and of short duration, making generalisation difficult. Increasing numbers of survivors of childhood cancer treated with anthracyclines will experience cardiac damage and require long-term surveillance and management. This will have an impact on cardiac services and costs. Diverse medical problems and other late sequelae that affect cardiac outcome will have an impact on other specialist services. Mechanisms to reduce or prevent cardiotoxicity from anthracycline therapy and cardiac markers to improve monitoring could alter the extent of this impact on service provision. RCTs of the different methods for reducing or preventing cardiotoxicity in children treated with anthracyclines for cancer with long-term follow-up are needed to determine whether the technologies influence the development of cardiac damage. Cost-effectiveness research is also required.

Topics: Anthracyclines; Antibiotics, Antineoplastic; Biomarkers; Cardiovascular Agents; Child; Drug Administration Schedule; Heart Diseases; Heart Failure; Humans; Lymphoma, Non-Hodgkin; Precursor Cell Lymphoblastic Leukemia-Lymphoma

The use of anthracyclines in the treatment of acute lymphoblastic leukemia is limited by associated cardiotoxic effects, which can result in cardiomyopathy and congestive heart failure, and may be irreversible. Anthracycline-induced cardiotoxicity in long-term survivors of childhood cancer is characterized by reduced left ventricular wall thickness and mass, which is indicative of decreased cardiac muscle and depressed left ventricular contractility which is indicative of unhealthy heart muscle. Risk factors for anthracycline-induced cardiotoxicity include high cumulative anthracycline doses, high anthracycline dose intensity, and radiotherapy. Radiotherapy in patients with cancer treated with anthracyclines can exacerbate anthracycline-induced cardiac tissue damage. Several studies have shown that cardiomyopathy disease progression can be delayed in adults by using angiotensin-converting enzyme inhibitors such as enalapril. Studies in long-term survivors of pediatric cancer showed that enalapril has significant benefits in preventing cardiac functional deterioration on a short-term basis, but this is not sustained. Anthracycline-associated cardiotoxic effects can be combatted by preventing cardiac injury during chemotherapy administration. There is evidence that dexrazoxane significantly reduces the cardiotoxicity associated with anthracyclines such as daunorubicin, doxorubicin, and epirubicin in adult patients with a wide range of tumor types. A study of the efficacy of dexrazoxane in reducing doxorubicin-induced cardiotoxicity in children and adolescents with high-risk acute lymphoblastic leukemia, showed that significantly fewer dexrazoxane-treated patients (21%) had elevated serum cardiac troponin (a biomarker of acute myocardial injury) levels than patients treated with chemotherapy alone (50%; P <.001). Dexrazoxane was also shown to have no effect on the event-free survival rate at 2.5 years, emphasizing that it does not detrimentally affect the efficacy of anthracycline therapy.

Topics: Adolescent; Adult; Anthracyclines; Antineoplastic Agents; Cardiomyopathies; Cardiovascular Agents; Child; Disease Progression; Heart; Heart Failure; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Razoxane; Risk Factors; Survivors

Doxorubicin chemotherapy is associated with cardiomyopathy. Dexrazoxane reduces cardiac damage during treatment with doxorubicin in children with acute lymphoblastic leukaemia (ALL). We aimed to establish the long-term effect of dexrazoxane on the subclinical state of cardiac health in survivors of childhood high-risk ALL 5 years after completion of doxorubicin treatment.. Between January, 1996, and September, 2000, children with high-risk ALL were enrolled from nine centres in the USA, Canada, and Puerto Rico. Patients were assigned by block randomisation to receive ten doses of 30 mg/m² doxorubicin alone or the same dose of doxorubicin preceded by 300 mg/m² dexrazoxane. Treatment assignment was obtained through a telephone call to a centralised registrar to conceal allocation. Investigators were masked to treatment assignment but treating physicians and patients were not; however, investigators, physicians, and patients were masked to study serum cardiac troponin-T concentrations and echocardiographic measurements. The primary endpoints were late left ventricular structure and function abnormalities as assessed by echocardiography; analyses were done including all patients with data available after treatment completion. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00165087.. 100 children were assigned to doxorubicin (66 analysed) and 105 to doxorubicin plus dexrazoxane (68 analysed). 5 years after the completion of doxorubicin chemotherapy, mean left ventricular fractional shortening and end-systolic dimension Z scores were significantly worse than normal for children who received doxorubicin alone (left ventricular fractional shortening: -0·82, 95% CI -1·31 to -0·33; end-systolic dimension: 0·57, 0·21-0·93) but not for those who also received dexrazoxane (-0·41, -0·88 to 0·06; 0·15, -0·20 to 0·51). The protective effect of dexrazoxane, relative to doxorubicin alone, on left ventricular wall thickness (difference between groups: 0·47, 0·46-0·48) and thickness-to-dimension ratio (0·66, 0·64-0·68) were the only statistically significant characteristics at 5 years. Subgroup analysis showed dexrazoxane protection (p=0·04) for left ventricular fractional shortening at 5 years in girls (1·17, 0·24-2·11), but not in boys (-0·10, -0·87 to 0·68). Similarly, subgroup analysis showed dexrazoxane protection (p=0·046) for the left ventricular thickness-to-dimension ratio at 5 years in girls (1·15, 0·44-1·85), but not in boys (0·19, -0·42 to 0·81). With a median follow-up for recurrence and death of 8·7 years (range 1·3-12·1), event-free survival was 77% (95% CI 67-84) for children in the doxorubicin-alone group, and 76% (67-84) for children in the doxorubicin plus dexrazoxane group (p=0·99).. Dexrazoxane provides long-term cardioprotection without compromising oncological efficacy in doxorubicin-treated children with high-risk ALL. Dexrazoxane exerts greater long-term cardioprotective effects in girls than in boys.. US National Institutes of Health, Children's Cardiomyopathy Foundation, University of Miami Women's Cancer Association, Lance Armstrong Foundation, Roche Diagnostics, Pfizer, and Novartis.

Topics: Adolescent; Antibiotics, Antineoplastic; Biomarkers; Canada; Cardiomyopathies; Cardiovascular Agents; Child; Child, Preschool; Disease-Free Survival; Doxorubicin; Female; Humans; Kaplan-Meier Estimate; Male; Myocardial Contraction; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Puerto Rico; Razoxane; Risk Assessment; Risk Factors; Survivors; Time Factors; Treatment Outcome; Troponin T; Ultrasonography; United States; Ventricular Function, Left; Young Adult

Doxorubicin chemotherapy is very effective in children with acute lymphoblastic leukemia (ALL) but also injures myocardial cells. Dexrazoxane, a free-radical scavenger, may protect the heart from doxorubicin-associated damage.. To determine whether dexrazoxane decreases doxorubicin-associated injury of cardiomyocytes, we randomly assigned 101 children with ALL to receive doxorubicin alone (30 mg per square meter of body-surface area every three weeks for 10 doses) and 105 to receive dexrazoxane (300 mg per square meter) followed immediately by doxorubicin. Serial measurements of serum cardiac troponin T were obtained in 76 of 101 patients in the doxorubicin group and 82 of 105 patients in the group given dexrazoxane and doxorubicin. A total of 2377 serum samples (mean, 15.1 samples per patient) were obtained before, during, and after treatment with doxorubicin. Troponin T levels were evaluated in a blinded fashion to determine whether they were elevated (>0.01 ng per milliliter)--the primary end point--or extremely elevated (>0.025 ng per milliliter).. Elevations of troponin T occurred in 35 percent of the patients (55 of 158). Patients treated with doxorubicin alone were more likely than those who received dexrazoxane and doxorubicin to have elevated troponin T levels (50 percent vs. 21 percent, P<0.001) and extremely elevated troponin T levels (32 percent vs. 10 percent, P<0.001). The median follow-up was 2.7 years. The rate of event-free survival at 2.5 years was 83 percent in both groups (P=0.87 by the log-rank test).. Dexrazoxane prevents or reduces cardiac injury, as reflected by elevations in troponin T, that is associated with the use of doxorubicin for childhood ALL without compromising the antileukemic efficacy of doxorubicin. Longer follow-up will be necessary to determine the influence of dexrazoxane on echocardiographic findings at four years and on event-free survival.

Topics: Antibiotics, Antineoplastic; Cardiomyopathies; Cardiovascular Agents; Chelating Agents; Child; Disease-Free Survival; Doxorubicin; Echocardiography; Female; Heart; Humans; Logistic Models; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Razoxane; Troponin T; Ventricular Function, Left

A case is presented to illustrate a potential effect of Chinese herbal medicine (CHM) formulas in treating chemotherapy-induced cardiotoxicity.. An 18-year-old adolescent male with refractory acute lymphoblastic leukemia (ALL) had experienced anthracycline-induced congestive heart failure (CHF) for 3 weeks. Under intensive care with conventional therapy, the patient still had exercise intolerance and depended on supplemental oxygen all day. Therefore, he consented to treatment with traditional Chinese medicine (TCM) for alternative therapy.. This patient was treated with modified Zhi Gan Cao Tang (ZGCT), three times a day for 2 months. After 6 days of CHM treatment, the patient could tolerate daily activity without supplemental oxygen. After 2 months of CHM treatment, the follow-up chest X-ray showed great improvements in pulmonary edema and cardiomegaly.. In this case, anthracycline-induced cardiotoxicity resolved slowly following the administration of modified ZGCT. It is suggested that the CHM formula has a protective effect on the progression of CHF secondary to the use of anthracyclines in pediatric cancer. Further studies to determine the mechanism and clinical trials are warranted.

Topics: Adolescent; Antineoplastic Agents; Cardiovascular Agents; Drugs, Chinese Herbal; Heart Failure; Humans; Male; Medicine, Chinese Traditional; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Cardiovascular Agents; Child; Doxorubicin; Female; Heart Diseases; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Randomized Controlled Trials as Topic; Razoxane; Sex Characteristics

The objective was to assess the cardiac effects of growth hormone (GH) therapy. Anthracycline-treated childhood cancer survivors frequently have reduced left ventricular (LV) wall thickness and contractility, and GH therapy may affect these factors.. We examined serial cardiac findings for 34 anthracycline-treated childhood cancer survivors with several years of GH therapy and baseline cardiac z scores similar to those of a comparison group (86 similar cancer survivors without GH therapy).. LV contractility was decreased among GH-treated patients before, during, and after GH therapy (-1.08 SD below the age-adjusted population mean before therapy and -1.88 SD 4 years after therapy ceased, with each value depressed below normal). Contractility was higher in the control group than in the GH-treated group, with this difference being nearly significant. The GH-treated children had thinner LV walls before GH therapy (-1.38 SD). Wall thickness increased during GH therapy (from -1.38 SD to -1.09 SD after 3 years of GH therapy), but the effect was lost shortly after GH therapy ended and thickness diminished over time (-1.50 SD at 1 year after therapy and -1.96 SD at 4 years). During GH therapy, the wall thickness for the GH-treated group was greater than that for the control group; however, by 4 years after therapy, there was no difference between the GH-treated group and the control group.. GH therapy among anthracycline-treated survivors of childhood cancer increased LV wall thickness, but the effect was lost after therapy was discontinued. The therapy did not affect the progressive LV dysfunction.

Topics: Adolescent; Angiotensin-Converting Enzyme Inhibitors; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Body Height; Cardiovascular Agents; Child; Child, Preschool; Enalapril; Female; Heart Ventricles; Hemodynamics; Human Growth Hormone; Humans; Hypertrophy, Left Ventricular; Hypopituitarism; Infant; Male; Myocardial Contraction; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survivors; Ultrasonography; Ventricular Dysfunction, Left

Topics: Antibiotics, Antineoplastic; Cardiomyopathies; Cardiovascular Agents; Disease-Free Survival; Doxorubicin; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Razoxane; Remission Induction

Topics: Antibiotics, Antineoplastic; Cardiomyopathies; Cardiovascular Agents; Chelating Agents; Child; Clinical Trials as Topic; Disease-Free Survival; Doxorubicin; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Razoxane; Troponin T

Circulatory disturbances may occur during and after the treatment of acute lymphoblastic leukemia (ALL). The reasons are: leukemic infiltrations of the heart, anaemia, renal disturbances, infections, cardiotoxic drugs, especially anthracyclines (Atc). The aim of the study was echocardiographic assessment of circulatory system in patients during and 3-5 years after ALL therapy in childhood. The study group (group B) consisted of 20 children, aged 1-16 years, who underwent Atc treatment with cumulative doses 155.8-330 mg/m2 and cardioprotective agent--dexrazoxane. In this group echocardiography was performed before the treatment as well as after 1, 6, 12 months and 3 years. The retrospective group (R) consisted of 36 persons aged 12-24 years, examined 3-5 years after the completion of ALL treatment, who had undergone the treatment with Atc in doses 148.6-416.7 mg/m2 without cardioprotection. The control group (K) consisted of 28 healthy volunteers, aged 9-25 years. In all subjects echocardiography was performed, standard measurements taken, systolic and diastolic indices of left ventricle (LV) function calculated. In patients during and 3-5 years after the treatment neither LV dilatation nor abnormal wall-thickness was found. The systolic indices remained normal. In the group B echocardiographic indices did not change significantly during 3 years of treatment and did not correlate with growing cumulative Atc doses. In this group isovolumetric relaxation time (IVRT) was significantly longer, what emphasized the need of further clinical and echocardiographic follow-up.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cardiovascular Agents; Case-Control Studies; Child; Child, Preschool; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Echocardiography; Female; Heart Diseases; Humans; Infant; Male; Paclitaxel; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Razoxane; Taxoids; Time Factors; Ventricular Function, Left; Ventricular Function, Right

The purpose of the presented study was to define the exercise tolerance in patients after acute lymphoblastic leukemia (ALL) treatment in childhood. Three groups of persons were examined: group A: 20 children, aged 7-19 years (mean 12.4 y), examined immediately after ALL therapy completion, with cumulative anthracycline (ATC) doses administered 155.8-300 mg/m2 and dexrazoxane, as cardioprotectant, group B: 36 patients, aged 12-24 years (mean 15.9), being 3-5 years after ALL treatment, who received ATC in cumulative doses 148.6-416.7 mg/m2, without cardioprotection, group C: 28 healthy volunteers, aged 9-25 years (mean 17.3), as controls. All the examined patients belonged to NYHA functional class I. In all subjects the exercise treadmill test was performed according to modified Bruce protocol. The parameters analysed were: MET--number of metabolic effort units achieved at the test, HRmax--maximal heart rate during exercise, %HRmax--percent of maximal HR for given patient's age achieved during the STdep--depression of ST segment in electrocardiography (ECG) immediately after the maximal exercise. During the exercise members of all 3 groups achieved the required HRmax without serious complaints and ECG abnormalities. Examined persons in group A,B and C presented with effort levels (MET), %HRmax, STdep that did not differ significantly. Only HRmax in groups A and C were higher than that achieved by members of group B.

Topics: Adolescent; Adult; Antibiotics, Antineoplastic; Cardiovascular Agents; Case-Control Studies; Child; Electrocardiography; Exercise Test; Exercise Tolerance; Female; Heart; Humans; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Razoxane; Time Factors