Cumulative Doxorubicin Research Articles

Chronic Progressive Cardiac Dysfunction Years After Doxorubicin Therapy for Childhood Acute Lymphoblastic Leukemia

Cross-sectional studies show that cardiac abnormalities are common in long-term survivors of doxorubicin-treated childhood malignancies. Longitudinal data, however, are rare. Serial echocardiograms (N = 499) were obtained from 115 doxorubicin-treated long-term survivors of childhood acute lymphoblastic leukemia (median age at diagnosis, 4.8 years; median follow-up after completion of doxorubicin, 11.8 years). Results were expressed as z scores to indicate the number of standard deviations (SDs) above (+) or below (-) the normal predicted value. Median individual and cumulative doxorubicin doses were 30 mg/m2 per dose and 352 mg/m2, respectively. Left ventricular fractional shortening was significantly reduced after doxorubicin therapy, and the reduction was related to cumulative dose. z scores for fractional shortening transiently improved before falling to -2.76 more than 12 years after diagnosis. Reduced fractional shortening was related to impaired contractility and increasing afterload, consequences of a progressive reduction of ventricular mass, and wall thickness relative to body-surface area. Left ventricular contractility fell significantly over time and was depressed at last follow-up in patients receiving more than 300 mg/m2 of doxorubicin. Systolic and diastolic blood pressures were below normal more than 9 years after diagnosis. Even patients receiving lower cumulative doxorubicin doses experienced reduced mass and dimension. Fractional shortening and dimension at the end of therapy predicted these parameters 11.8 years later. Cardiac abnormalities were persistent and progressive after doxorubicin therapy. Inadequate ventricular mass with chronic afterload excess was associated with progressive contractile deficit and possibly reduced cardiac output and restrictive cardiomyopathy. The deficits were worst after highest cumulative doses of doxorubicin, but appeared even after low doses.

First-line chemotherapy of advanced or metastatic breast cancer (MBC) with docetaxel and doxorubicin in Indonesia: results from A phase II trial

Doxorubicin and docetaxel as a single agent are known as active cytotoxic agents for the treatment of metastatic breast cancer (MBC). Their combination has also shown to be highly active as a second-line chemotherapy of MBC. This study was design to evaluate the efficacy and safety of docetaxel-doxorubicin combination as first line chemotherapy of MBC patients in Indonesia. Twenty-six female patients between 31-65 years old with advanced or MBC was enrolled. No prior taxane or cumulative doxorubicin of 250 mg/m2 was allowed and patients should not have a heart disease. Treatment consisted of doxorubicin 50 mg/m2 as intravenous (IV) bolus followed one hour later by docetaxel 60 mg/m2 by IV infusion over 1 hour every 3 weeks for 6 cycles. Premedication with oral corticosteroid was administered a day prior to chemotherapy until the second day of each cycle. Left ventricular ejection fraction was recorded at baseline and after the 6th cycle. At the end of study, a total of 156 cycles of chemotherapy have been delivered. Five and 11 patients had a complete response (CR) and partial response (PR), respectively, which accounted for a 61.54% best overall response. Three patients with extensive liver metastases showed complete disappearance after 6 cycles. Most frequent grade 3-4 toxicities were leukopenia (80.77%) and febrile neutropenia (5.77%). Leukopenia was usually short in duration, occurred mainly during the first and second cycle and did not require dose reduction. No patient developed heart failure. There was one death due to progressive disease after 6 cycles. Combination of doxorubicin 50 mg/m2 and docetaxel 60 mg/m2 was sufficiently active as first-line chemotherapy of MBC, especially in patients with liver metastases, with a manageable toxicity profile. (Med J Indones 2005; 14: 20-5)   Keywords: docetaxel, doxorubicin, advanced or metastatic breast cancer, phase II trial, anthracycline and taxane combination

Dexrazoxane

Dexrazoxane (Cardioxane, Zinecard, a cyclic derivative of edetic acid, is a site-specific cardioprotective agent that effectively protects against anthracycline-induced cardiac toxicity. Dexrazoxane is approved in the US and some European countries for cardioprotection in women with advanced and/or metastatic breast cancer receiving doxorubicin; in other countries dexrazoxane is approved for use in a wider range of patients with advanced cancer receiving anthracyclines. As shown in clinical trials, intravenous dexrazoxane significantly reduces the incidence of anthracycline-induced congestive heart failure (CHF) and adverse cardiac events in women with advanced breast cancer or adults with soft tissue sarcomas or small-cell lung cancer, regardless of whether the drug is given before the first dose of anthracycline or the administration is delayed until cumulative doxorubicin dose is > or =300 mg/m2. The drug also appears to offer cardioprotection irrespective of pre-existing cardiac risk factors. Importantly, the antitumour efficacy of anthracyclines is unlikely to be altered by dexrazoxane use, although the drug has not been shown to improve progression-free and overall patient survival. At present, the cardioprotective efficacy of dexrazoxane in patients with childhood malignancies is supported by limited data. The drug is generally well tolerated and has a tolerability profile similar to that of placebo in cancer patients undergoing anthracycline-based chemotherapy, with the exception of a higher incidence of severe leukopenia (78% vs 68%; p < 0.01). Dexrazoxane is the only cardioprotective agent with proven efficacy in cancer patients receiving anthracycline chemotherapy and is a valuable option for the prevention of cardiotoxicity in this patient population.

Myocardial performance index combining systolic and diastolic myocardial performance in doxorubicin-treated patients and its correlation to conventional echo/Doppler indices.

This study was designed to evaluate the utility of myocardial performance index (MPI) in anthracycline cardiotoxicity. The MPI measures the ratio of total time spent in isovolumic activity (isovolumetric contraction time and isovolumetric relaxation time) to the ejection time, thus giving a global index combining systolic and diastolic myocardial performance. In this study, MPI was measured in 35 doxorubicin-treated children (aged 108.5+/-55.31 months, 23 males and 12 females) in sinus rhythm and 32 age-matched controls, and it was compared with conventional Doppler echocardiographic parameters. The isovolumetric contraction time was prolonged (38.37+/-24.43 vs 26.37+/-15.53, p <0.02) and ejection time was shortened (231.91 +/- 28.87 vs 256.21+/-19.55, p<0.001) in doxorubicin-treated patients compared to that in normal children. The isovolumetric relaxation time did not show significant difference between patients and control group (60.11+/-10.92 vs 61.06+/-12.12, p>0.05). MPI was significantly increased in doxorubicin-treated patients compared with that in control groups (0.42+/-0.07 vs 0.34+/-0.06, p<0.001), and significant correlation was observed between MPI and fractional shortening, ejection fraction, and left ventricular end diastolic and end systolic diameters (respectively, r = -0.508, p <0.002; r = -0.532, p<0.001; r = 0.467 p<0.005; r=0.606, p<0.001). Also, a weak correlation was found between MPI and duration of the disease and patient ages (r = 0.393, p < 0.02; r = 0.379; p < 0.02). However, there was no correlation between MPI and cumulative doxorubicin dose (r = 0.311, p > 0.05) and diastolic Doppler parameters in doxorubicin-treated patients. We think that MPI may be a useful parameter in monitoring left ventricular dysfunction in anthracyline-treated patients.

Early decline in left ventricular ejection fraction predicts doxorubicin cardiotoxicity in lymphoma patients.

Thirty adult patients with non-Hodgkin's lymphoma were studied to evaluate prospectively the significance of early decline in left ventricular ejection fraction after low cumulative doxorubicin dose (200 mg m−2) in predicting the later impairment of left ventricular function. Cardiac function was monitored with radionuclide ventriculography at baseline and after cumulative doxorubicin doses of 200, 400 and 500 mg m−2. Cardiotoxicity was defined as a decrease in left ventricular ejection fraction of more than 10% units to a final left ventricular ejection fraction ⩽50%. Twenty-eight patients received doxorubicin ⩾400 mg m−2 and were evaluable for cardiotoxicity. Clinical heart failure developed in two patients (7%) after a cumulative doxorubicin dose of 500 mg m−2. Left ventricular ejection fraction decreased more than 10% absolute ejection fraction units to a final left ventricular ejection fraction ⩽50% in 10 patients (36%). Left ventricular ejection fraction decreased from 56±1.5% to 53.6±1.5% (P=0.016) in patients with no cardiotoxicity, and from 60.8±2.4% to 41.8±2.0% (P<0.001) in patients with cardiotoxicity. For patients who developed cardiotoxicity, the fall in left ventricular ejection fraction after a cumulative doxorubicin dose of only 200 mg m−2 was highly significant (left ventricular ejection fraction 49.7±1.8%, P=0.001 vs baseline). In receiver operator characteristic analysis, the area under the curve for the decrease in left ventricular ejection fraction at a cumulative doxorubicin dose of 200 mg m−2 for predicting cardiotoxicity in all patients was 0.858. The decrease in left ventricular ejection fraction of more than 4% units after a cumulative doxorubicin dose of 200 mg m−2 had a 90% sensitivity and 72% specificity for predicting later cardiotoxicity. Our results show that the significant impairment of left ventricular function during doxorubicin therapy can be predicted early, already at low cumulative doxorubicin doses. This finding may be of value in identifying patients at high or low risk for the development of anthracycline cardiotoxicity.British Journal of Cancer (2002) 86, 1697–1700. doi:10.1038/sj.bjc.6600346 www.bjcancer.com© 2002 Cancer Research UK

EORTC 10968: a phase I clinical and pharmacokinetic study of polyethylene glycol liposomal doxorubicin (Caelyx®, Doxil®) at a 6-week interval in patients with metastatic breast cancer

BackgroundWe performed a phase I study of polyethylene glycol (pegylated, Stealth®) liposomal doxorubicin (Caelyx®, Doxil®) using a prolonged (6-week) dose interval to reduce the incidence of skin toxicity that was dose-limiting at more conventional dose intervals, and which appeared to be schedule dependent. Patients and methodsEligible for the study were metastatic breast cancer patients who had received a maximum of one prior therapy for metastatic disease. The defined dose levels were 60, 70, 80 and90 mg/m2. ResultsTwenty patients were assessed at starting doses of 60 mg/m2 (n = 9) or 70 mg/m2 (n = 11). The dose-limiting toxicity was mucositis. Severe skin toxicity was not observed at the 60 mg/m2 dose level, and occurred in only one patient treated at 70 mg/m2. Significant neutropenia, alopecia, and nausea and vomiting were rare events. No clinical cardiac events occurred, despite a median cumulative doxorubicin dose of 323 mg/m2 (range 5–630 mg/m2). Partial responses were documented in five patients. Pharmacokinetics were assessed in 15 patients, and confirmed the long terminal half-life of the agent (median 77 h) demonstrated in earlier studies. ConclusionsThe recommended dose of Caelyx®/Doxil® using this schedule is 60 mg/m2 every 6 weeks. This is a safe and effective regimen that permits prolonged administration of anthracycline to patients with metastatic breast cancer.

Multicentre analysis of anthracycline-induced cardiotoxicity in children following treatment according to the nephroblastoma studies SIOP No.9/GPOH and SIOP 93-01/GPOH.

To study cardiac function and the incidence of anthracycline-induced cardiotoxicity in children following treatment according to the nephroblastoma studies SIOP No.9/GPOH and SIOP 93-01/GPOH. Analysis of clinical status, echocardiography, and ECG findings prior to administration of anthracyclines (median cumulative doxorubicin dose: 250 mg/m(2) [range: 90-411 mg/m(2)] and after a median posttherapeutic interval of 2.9 years [range: 0-10.2 years]. Data on cardiac function before and/or after therapy could be obtained of 186 patients. Posttherapy left ventricular fractional shortening was reduced in 4/157 (2.5%) patients. Out of the 4 children, 2 had clinically reduced tolerance to exercise and received anticongestive therapy. Abnormal ECG findings that were not detectable prior to therapy were found in 7/124 (5.6%) children. The incidence of abnormal findings is low in our study group in comparison to data from the literature and might be due to the comparably short posttherapeutic interval.

Natriuretic peptides during the development of doxorubicin-induced left ventricular diastolic dysfunction.

To investigate changes in plasma atrial natriuretic peptide (ANP), N-terminal pro-atrial natriuretic peptide (NT-pro-ANP) and brain natriuretic peptide (BNP) during the development of doxorubicin-induced left ventricular systolic and diastolic dysfunction as measured by echocardiography (ECHO). Prospective study. University hospital. Twenty-eight adult patients with non-Hodgkin's lymphoma, who received doxorubicin to the cumulative dose of 400-500 mg m(-2). The relationship between plasma natriuretic peptides and systolic and diastolic ECHO indices after the cumulative doxorubicin doses of 200, 400 and 500 mg m(-2). Left ventricular ejection fraction (LVEF, by 2D ECHO) decreased from 58 +/- 1.7 to 52.5 +/- 1.3% (P=0.036) and fractional shortening (FS) from 34.6 +/- 1.4 to 27.8 +/- 0.9% (P=0.002). Peak E wave velocity decreased from 63.3 +/- 3.2 to 51.3 +/- 2.6 cm s(-1) (P=0.008) resulting in a statistically nonsignificant decrease in E/A ratio from 1.08 +/- 0.01 to 0.85 +/- 0.07. A significant decrease was observed in the percentage of left ventricular filling during the 1/3 of diastole (1/3FF) from 42.2 +/- 1.7 to 36.5 +/- 2.0% (P < 0.001). LV end systolic diameter increased from 32 +/- 1 to 38 +/- 1 mm (P=0.011), whereas left atrial (LA) diameter remained unchanged. Peak filling rate decreased from 4.4 +/- 0.2 to 4.0 +/- 0.2 stroke volume s(-1) (SV s(-1)) (ns). Plasma levels of ANP increased from 16.4 +/- 1.3 to 22.7 +/- 2.4 pmol L(-1) (P=0.002), NT-pro-ANP from 288 +/- 22 to 380 +/- 42 pmol L(-1) (P=0.019) and BNP from 3.3 +/- 0.4 to 8.5 +/- 2.0 pmol L(-1) (P=0.020). There was a significant inverse correlation between the decrease in FS and the increases in plasma NT-pro-ANP (r= -0.524, P=0.018) and plasma BNP (r=0.462, P=0.04) and between the decrease in PFR and the increases in plasma ANP (r= -0.457, P=0.043) and plasma NT-pro-ANP (r= -0.478, P=0.033). Furthermore, after doxorubicin therapy, significant inverse correlations were observed between E/A ratio and plasma ANP (r= -0.535, P=0.008), between E/A ratio and plasma NT-pro-ANP (r= -0.432, P=0.04) and between E/A ratio and plasma BNP (r= -0.557, P=0.006) as well as between 1/3FF and plasma BNP (r= -0.493, P=0.017). There was also a trend for correlation between LA diameter and plasma BNP (r=0.395, P=0.062) and peak E wave velocity and plasma BNP (r= -0.414, P=0.05), respectively. However, no significant correlations were observed between any of the systolic parameters and natriuretic peptide levels. The results of this prospective study show that during the evolution of doxorubicin-induced LV dysfunction the secretion of natriuretic peptides is more closely associated with the impairment of left ventricular diastolic filling than with the deterioration of LV systolic function.

Concomitant Impairment of Left Ventricular Systolic and Diastolic Function During Doxorubicin Therapy: A Prospective Radionuclide Ventriculographic and Echocardiographic Study

Thirty adult lymphoma patients were studied prospectively with serial radionuclide ventriculography (RVG) and echocardiography (ECHO) to investigate whether changes in left ventricular (LV) diastolic function precede the impairment of LV systolic function during doxorubicin therapy. The patients received 8-10 cycles of CHOP to a cumulative doxorubicin dose of 400-500 mg/m 2. RVG and ECHO were performed at baseline and after cumulative doxorubicin doses of 200, 400 and 500 mg/m 2. Left ventricular ejection fraction (LVEF) decreased from 58 ± 1.3 to 49.6 ± 1.7% (p <0.001) and from 58 ± 1.7 to 52.5 ± 1.3% (p =0.036) as assessed with RVG and 2D ECHO, respectively. Of the diastolic ECHO doppler indices peak E wave velocity decreased from 63.3 ± 3.2 to 51.3 ± 2.6 cm/s (p =0.008) and LV filling during the first 1/3 of diastole (1/3FF) from 42.2 ± 1.7 to 36.5 ± 2.0% (p <0.001). The decrease in LVEF was statistically significant after the cumulative doxorubicin dose of 200 mg/m 2 as assessed with RVG and after 400 mg/m 2 as assessed with 2D ECHO. The decrease in 1/3FF reached the statistical significance after the cumulative doxorubicin dose of 400 mg/m 2 and the decrease in peak E wave velocity after 500 mg/m 2. This study shows that during doxorubicin therapy there are significant changes both in systolic and diastolic LV function. In addition, these changes manifest at relatively low cumulative doxorubicin doses and occur concomitantly. Thus, the assessment of diastolic function provides no advantage over monitoring systolic function during doxorubicin therapy.

Clinical and economic impact of multiple gated acquisition scan monitoring during anthracycline therapy.

The clinical and economic impacts of monitoring cardiac function in patients given doxorubicin have yet to be determined, especially in relation to patient age, cumulative doxorubicin dose, and the relative efficacies of doxorubicin-based vs alternative regimens. We developed a decision analysis model that includes these factors to estimate the incremental survival benefit and cost-effectiveness of using multiple gated acquisition scans to measure left-ventricular ejection fraction before and during doxorubicin chemotherapy. Probability distributions for the incidences of abnormal left-ventricular ejection fraction findings and congestive heart failure were derived from a retrospective review of 227 consecutive cases at The University of Michigan Medical Center and published findings. Multiple gated acquisition-scan monitoring minimally improved the probability of 5-year survival (<1.5% in the base–case scenario). For patients who received up to 350 mg m−2 of doxorubicin, multiple gated acquisition-scan screening had an incremental cost of $425 402 per life saved for patients between the ages of 15–39. This incremental cost markedly decreased to $138 191, for patients between the ages of 40–59, and to $86 829 for patients older than 60 years. The small gain in 5-year survival probability secondary to multiple gated acquisition scan monitoring doubled for all age groups when the average cumulative dose for doxorubicin reached 500 mg m−2. Variations in the cure rate differences between the doxorubicin and alternative regimens had insignificant effects on the improvement in 5-year survival rates from multiple gated acquisition-scan screening. The use of multiple gated acquisition scans for pretreatment screening appears to be more cost-effective for patients who are 40 years or older, when cumulative doxorubicin dose is 350 mg m−2 or less.British Journal of Cancer (2002) 86, 226–232. DOI: 10.1038/sj/bjc/6600037 www.bjcancer.com© 2002 The Cancer Research Campaign

Neuroendocrine changes during the evolution of doxorubicin-induced left ventricular dysfunction in adult lymphoma patients

Doxorubicin-induced cardiotoxicity was used as a model to prospectively investigate neuroendocrine changes during the development of left ventricular dysfunction. Radionuclide ventriculography, frequency domain analysis of heart rate variability (HRV), and plasma noradrenaline and natriuretic peptide measurements were performed in 27 adult lymphoma patients at baseline and after cumulative doxorubicin doses of 200, 400 and 500 mg/m(2). The left ventricular ejection fraction (LVEF) decreased from 58.1+/-1.4% to 50.3+/-1.1% (P<0.001) and 49.3+/-1.7% (P<0.001) after cumulative doxorubicin doses of 400 and 500 mg/m(2) respectively. With a doxorubicin dose of up to 400 mg/m(2) there was an increase in sympathetic tone, characterized by a decrease in the normalized high-frequency (HF(nu)) power (P=0.011), and increases in the normalized low-frequency (LF(nu)) power (P=0.011), the LF/HF ratio (P=0.021) and the plasma noradrenaline concentration (P=0.034). The decrease in LVEF was correlated with the changes in LF(nu) and HF(nu) power (r=0.540, P=0.012) and LF/HF ratio (r=-0.452, P=0.04). However, after the cumulative doxorubicin dose of 500 mg/m(2) the changes in HRV components and plasma noradrenaline levels returned towards baseline. This was accompanied by increased concentrations of plasma atrial natriuretic peptide (P=0.004) and brain natriuretic peptide (P=0.021). Our findings suggest that doxorubicin-induced left ventricular dysfunction is associated with an early change in sympathovagal balance towards sympathetic predominance. Along with further progression of left ventricular dysfunction, there is an attenuation of sympathetic tone, which may be attributable to sympatho-adrenal inhibition by increased secretion of natriuretic peptides.

Congestive heart failure after treatment for Wilms' tumor: a report from the National Wilms' Tumor Study group.

We determined the frequency of and risk factors for congestive heart failure following treatment for Wilms' tumor that included doxorubicin. Flow sheets and medical records were reviewed to identify cases of congestive heart failure in a cohort of patients treated on National Wilms' Tumor Studies (NWTS)-1, -2, -3, and -4. The frequency of congestive heart failure was estimated using the Kaplan-Meier method. A case-control study was conducted to determine the relationship among cumulative doxorubicin dose, site(s), total dose of abdominal and thoracic irradiation, sex, and the frequency of congestive heart failure. The cumulative frequency of congestive heart failure was 4.4% at 20 years after diagnosis among patients treated initially with doxorubicin and 17.4% at 20 years after diagnosis among those treated with doxorubicin for their first or subsequent relapse of Wilms' tumor. The relative risk (RR) of congestive heart failure was increased in females (RR = 4.5; P =.004) and by cumulative doxorubicin dose (RR = 3.3/100 mg/m(2); P <.001), lung irradiation (RR = 1.6/10 Gy; P =.037), and left abdominal irradiation (RR = 1.8/10 Gy; P =.013). We conclude that congestive heart failure is a risk of treatment with doxorubicin for Wilms' tumor. Additional follow-up of those children treated on NWTS-4 will be necessary to determine if the decrease in dose to 150 mg/m(2) significantly reduces this risk.

Doxorubicin and Paclitaxel in the Treatment of Advanced Breast Cancer: Efficacy and Cardiac Considerations

Doxorubicin and paclitaxel are highly active agents in the treatment of advanced breast cancer. Although early trials of the combination reported high response rates, an unexpectedly high incidence of congestive heart failure observed on two of the early trials was cause for much concern. More recently, clinical trials that have limited the cumulative doxorubicin dose to 400 mg/m2 or below when given in combination with paclitaxel have not observed an increase in cardiac toxicity. In addition, a retrospective review of over 600 women with advanced breast cancer treated with doxorubicin and paclitaxel concluded that the combination could be administered safely up to a cumulative doxorubicin dose of 340–380 mg/m2.It is likely that a pharmacokinetic interaction between doxorubicin and paclitaxel is, in large part, responsible for the higher than expected incidence of congestive heart failure observed in some studies. It appears that paclitaxel decreases the clearance of doxorubicin by approximately 30% when the two drugs are administered in close succession.Because the use of combination of doxorubicin and paclitaxel may benefit women with advanced breast cancer, a review of pertinent clinical studies and the implications of the pharmacokinetic interaction is provided. Particular attention has been paid to cardiac toxicities.It can be concluded that the use of combination doxorubicin and paclitaxel is safe up to a cumulative doxorubicin dose of 340–380 mg/m2. This would allow for up to six courses of therapy with doxorubicin 60 mg/m2 and paclitaxel 175 mg/m2 by 3-hour infusion. Therapy can be continued with single-agent paclitaxel. In order to minimize cardiac risk, patients should be selected carefully and be monitored for adverse cardiac effects.

Correlation between serum levels of cardiac troponin-T and the severity of the chronic cardiomyopathy induced by doxorubicin.

To investigate, over a wide range of cumulative doxorubicin doses, the feasibility of using serum concentrations of cardiac troponin-T (cTnT) as a biomarker for doxorubicin-induced myocardial damage. Groups of spontaneously hypertensive rats (SHR) were given 1 mg/kg doxorubicin weekly for 2 to 12 weeks. Cardiomyopathy scores were assessed according to the method of Billingham and serum levels of cTnT were quantified by a noncompetitive immunoassay. Myocardial localization of cTnT was studied by immunohistochemical staining and confocal microscopy. Increases in serum levels of cTnT (0.03 to 0.05 ng/mL) and myocardial lesions (cardiomyopathy scores of 1 or 1.5) were found in one out of five and two out of five SHR given 2 and 4 mg/kg doxorubicin, respectively. All animals given 6 mg/kg or more of doxorubicin had increases in serum cTnT and myocardial lesions. The average cTnT levels and the cardiomyopathy scores correlated with the cumulative dose of doxorubicin (0.13 v 0.4 ng/mL cTnT and scores of 1.4 v 3.0 in SHR given 6 and 12 mg/kg doxorubicin, respectively). Decreased staining for cTnT was observed in cardiac tissue from SHR receiving cumulative doses that caused only minimal histologic alterations (scores of 1 to 1.5). Staining for cTnT decreased simultaneously with increases in the severity of the cardiomyopathy scores. cTnT is released from doxorubicin-damaged myocytes. Measurements of serum levels of this protein seem to provide a sensitive means for assessing the early cardiotoxicity of doxorubicin.

QT dispersion and late potentials during doxorubicin therapy for non-Hodgkin's lymphoma.

To investigate effects of doxorubicin therapy on cardiac electrophysiology, with special emphasis on QT dispersion and late potentials, in lymphoma patients. Prospective study. University hospital. Twenty-eight adult non-Hodgkin's lymphoma patients who received doxorubicin to a cumulative dose of 400-500 mg m-2. Standard 12-lead electrocardiogram (ECG) and signal-averaged ECG (SAECG) recordings were performed at baseline and after cumulative doxorubicin doses of 200, 400 and 500 mg m-2. Heart rate-corrected QT interval (QTc) increased from 402 +/- 4 to 416 +/- 5 ms (P = 0.002) during the study period. QT dispersion (variability in QT interval duration amongst the different leads of the standard 12-lead ECG) increased from 24.1 +/- 2.5 to 35.0 +/- 2.8 ms (P = 0.041) and QTc dispersion increased from 26.5 +/- 2.5 to 39.0 +/- 3.5 ms (P = 0.039). Five patients (18%) developed QT dispersion exceeding 50 ms. In addition, two patients (7%) developed late potentials during doxorubicin therapy. The changes in QTc duration, QT dispersion and late potentials occurred independently of the impairment of left ventricular function. Prolongation of QTc, increased QT dispersion and development of late potentials are indicative of doxorubicin-induced abnormal ventricular depolarization and repolarization. QT dispersion and late potentials are both known to be associated with increased risk of serious ventricular dysrhythmias and sudden death in various cardiac diseases. Thus, follow-up of these parameters might also be useful in assessing the risk of late cardiovascular events in cancer patients treated with anthracyclines.

Indium-111–Antimyosin Scintigraphy in the Early Detection of Heart Damage After Anthracycline Therapy in Children

To determine the value of indium-111-antimyosin ((111)In-AM) scintigraphy in the early detection of myocardial damage in children treated with doxorubicin. Twelve planar scintigrams were made of eight patients (seven children and one young adult; mean age, 12 years). Three scans were obtained before doxorubicin therapy in three patients, and nine scans were obtained during doxorubicin therapy in seven patients. The heart-to-lung ratio (HLR) was calculated. Left ventricular function was assessed by echocardiography before and during therapy by measuring the fractional shortening (FS). The HLR of the three baseline scans was below 1.5, within the normal range for adults. Six of the seven patients whose scans were obtained during chemotherapy had abnormal HLR values (> 1.5). One patient had severe myocyte damage and showed an early increase in the HLR (2.3) after a cumulative doxorubicin dose of 150 mg/m(2). The FS measured by echocardiography was normal throughout therapy, and the final cumulative dose of doxorubicin was 450 mg/m(2). This patient developed fatal clinical heart failure 3 months after completion of chemotherapy. In one patient, who was pretreated with the cardioprotective agent dexrazoxane, the HLR remained within normal limits during therapy. (111)In-AM scintigraphy seems to be suitable to detect early myocardial damage after a cumulative doxorubicin dose of 150 mg/m(2 )in children and may be useful for identifying children who are at increased risk of developing cardiac sequelae.

Natriuretic peptides as markers of cardiotoxicity during doxorubicin treatment for non-Hodgkin's lymphoma.

Thirty adult patients with non-Hodgkin's lymphoma who were planned to receive up to 8-10 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) to a cumulative doxorubicin dose of 400-500 mg/m2 were studied to evaluate the value of serial plasma atrial natriuretic peptide (ANP), N-terminal pro-ANP (NT-proANP) and brain natriuretic peptide (BNP) measurements in the early detection of doxorubicin-induced left ventricular dysfunction. Plasma levels of natriuretic peptides were measured before every treatment course and 4 wk after the last one. Cardiac function was monitored with serial radionuclide ventriculography. Twenty-eight patients were evaluable for cardiotoxicity. Clinical heart failure developed in 2 patients (7%). Left ventricular ejection fraction (LVEF) decreased from 58.0+/-1.3% to 49.6+/-1.7% (p <0.001). Plasma levels of ANP increased from 16.4+/-1.3 pmol/l to 22.7+/-2.4 pmol/l (p= 0.002), NT-proANP from 288+/-22 to 380+/-42 pmol/l (p = 0.019) and BNP from 3.3+/-0.4 to 8.5+/-2.0 pmol/l (p = 0.020). There was a significant correlation between the increase in plasma ANP and the decrease in LVEF (r = -0.447, p = 0.029), and a trend towards significance between the increase in NT-proANP and the decrease in LVEF (r=-0.390, p=0.059). The decrease in LVEF started very early and could already be seen after the cumulative doxorubicin dose of 200 mg/m2, whereas the increase in plasma natriuretic peptides was not evident until the cumulative doxorubicin dose of 400 mg/m2. Our results show that neuroendocrine activation - increased concentrations of plasma natriuretic peptides - occurs when left ventricular function has reduced substantially and its compensatory capacity has been exceeded resulting in atrial and ventricular overload. Thus, serial natriuretic peptide measurements cannot be used in predicting the impairment of left ventricular function. On the other hand, our study suggests that natriuretic peptides are useful in the detection of subclinical left ventricular dysfunction in patients receiving doxorubicin therapy.

Dexrazoxane: A New Cardioprotective Agent

Objective: To review the literature discussing the use of dexrazoxane (e.g., Zinecard, ICRF-187) to prevent doxorubicin-induced cardiotoxicity. Data Sources: Pertinent English-language reports of studies in humans were retrieved from a MEDLINE search (January 1980-January 1997); search terms included chelating agents, razoxane, dexrazoxane, Zinecard, ICRF-187, ADR-529, and ICRF-159. Study Selection: Representative articles discussing the chemistry, pharmacology, pharmacokinetics, dosing, and administration of dexrazoxane and those discussing clinical trials were selected. Data Extraction: Data were extracted and analyzed if the information was relevant and consistent. Studies were selected for review in the text on the basis of study design and clinical end points. Data Synthesis: Dexrazoxane is a chemoprotective agent developed to prevent cardiac tissue toxicity. Dexrazoxane exerts a cardioprotective effect with some clinically significant toxicities; it may also interfere with the antitumor activity of doxorubicin. Until there are sufficient data to support its use in first-line supportive care therapy, dexrazoxane should be reserved for use in patients responding to doxorubicin-based chemotherapy but who have risk factors for cardiac toxicity or have received a cumulative doxorubicin bolus dose of 300 mg/m2. Conclusions: The management of doxorubicin-induced cardiotoxicity has led to the development of supportive care drugs that specifically counteract the dose-limiting toxicities. Dexrazoxane may not completely eliminate the concern about doxorubicin-induced cardiotoxicity, but it may open new avenues for continuing doxorubicin-based chemotherapy.

The use of cardiac biopsy to demonstrate reduced cardiotoxicity in AIDS Kaposi’s sarcoma patients treated with pegylated liposomal doxorubicin

Pegylated liposomal doxorubicin (PL-DOX) has been shown in preclinical models to induce less cardiotoxicity than non-liposomal doxorubicin. Endomyocardial biopsy is a highly sensitive and specific method for detecting anthracycline-induced cardiac damage. Myocardial tissue from ten KS patients who had received cumulative PL-DOX (20 mg/m2/biweekly) of 440-840 mg/m2 was evaluated for evidence of anthracycline-induced cardiac damage. Controls were assembled from patients who had received cumulative doxorubicin doses of 174-671 mg/m2 in two earlier cardiac biopsy protocols. Two control groups were selected on the basis of both cumulative (+/- 10 mg/m2) and peak doxorubicin dose (60 or 20 mg/m2, control group 1), or peak dose alone (20 mg/m2, control group 2). PL-DOX patients had significantly lower biopsy scores compared with those of doxorubicin controls despite higher cumulative doses of anthracycline. The median biopsy scores for the PL-DOX and doxorubicin groups, respectively, were 0.3 vs. 3.0 (P = 0.002, Cochran-Mantel-Haenszel row mean difference test) for group 1 and 1.25 for group 2 (P < 0.001, Wilcoxon rank-sum test). Less severe cardiac changes were seen in patients given PL-DOX relative to historical control patients given comparable cumulative doses of doxorubicin.

Dexrazoxane. A review of its use as a cardioprotective agent in patients receiving anthracycline-based chemotherapy.

Dexrazoxane has been used successfully to reduce cardiac toxicity in patients receiving anthracycline-based chemotherapy for cancer (predominantly women with advanced breast cancer). The drug is thought to reduce the cardiotoxic effects of anthracyclines by binding to free and bound iron, thereby reducing the formation of anthracycline-iron complexes and the subsequent generation of reactive oxygen species which are toxic to surrounding cardiac tissue. Clinical trials in women with advanced breast cancer have found that patients given dexrazoxane (about 30 minutes prior to anthracycline therapy; dexrazoxane to doxorubicin dosage ratio 20:1 or 10:1) have a significantly lower overall incidence of cardiac events than placebo recipients (14 or 15% vs 31%) when the drug is initiated at the same time as doxorubicin. Cardiac events included congestive heart failure (CHF), a significant reduction in left ventricular ejection fraction and/or a > or = 2-point increase in the Billingham biopsy score. These results are supported by the findings of studies which used control groups (patients who received only chemotherapy) for comparison. The drug appears to offer cardiac protection irrespective of pre-existing cardiac risk factors. In addition, cardiac protection has been shown in patients given the drug after receiving a cumulative doxorubicin dose > or = 300 mg/m2. It remains to be confirmed that dexrazoxane does not affect the antitumour activity of doxorubicin: although most studies found that clinical end-points (including tumour response rates, time to disease progression and survival duration) did not differ significantly between treatment groups, the largest study did show a significant reduction in response rates in dexrazoxane versus placebo recipients. Dexrazoxane permits the administration of doxorubicin beyond standard cumulative doses; however, it is unclear whether this will translate into prolonged survival. Preliminary results (from small nonblind studies) indicate that dexrazoxane reduces cardiac toxicity in children and adolescents receiving anthracycline-based therapy for a range of malignancies. The long term benefits with regard to prevention of late-onset cardiac toxicity remain unclear. With the exception of severe leucopenia [Eastern Cooperative Oncology Group (ECOG) grade 3/4 toxicity], the incidence of haematological and nonhaematological adverse events appears similar in patients given dexrazoxane to that in placebo recipients undergoing anthracycline-based chemotherapy. Although preliminary pharmacoeconomic analyses have shown dexrazoxane to be a cost-effective agent in women with advanced breast cancer, they require confirmation. Dexrazoxane is a valuable drug for protecting against cardiac toxicity in patients receiving anthracycline-based chemotherapy. Whether it offers protection against late-onset cardiac toxicity in patients who received anthracycline-based chemotherapy in childhood or adolescence remains to be determined. Further clinical experience is required to confirm that it does not adversely affect clinical outcome, that it is a cost-effective option, and to determine the optimal treatment regimen.