Skip Navigation

European Journal of Heart Failure 2002 4(3):235-242; doi:10.1016/S1388-9842(01)00201-X
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Gharib, M.I.
Right arrow Articles by Burnett, A.K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gharib, M.I.
Right arrow Articles by Burnett, A.K.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2002 European Society of Cardiology

Chemotherapy-induced cardiotoxicity: current practice and prospects of prophylaxis

M.I. Gharib and A.K. Burnett*

Department of Haematology University of Wales College of Medicine, Heath Park, Cardiff CF14 4XW, UK

* Corresponding author. Telephone: +44-29-207-42375; fax: +44-29-207-44655. E-mail address: burnettak{at}cardiff.ac.uk


   Abstract
Top
 Abstract
1. Introduction
 2. Cytotoxic antibiotics
 3. Alkylating agents
 4. Other chemotherapeutic agents
 References
 
Cardiotoxicity is a potential side effect of few chemotherapeutic agents. The anthracycline class of cytotoxic antibiotics are the most famous, but other chemotherapeutic agents can also cause serious cardiotoxicity and are not so well recognised. Examples include cyclophosphamide, ifosfamide, mitomycin and fluorouracil. Prediction and hence prophylaxis has always been a difficult task. Ideal monitoring techniques, upon which efficient prophylaxis depends, are yet to be determined. Current prophylaxis relies upon early detection of systolic and/or diastolic dysfunction. While somewhat useful, in some cases by the time defects are detected progression of chemotherapy-induced cardiomyopathy is beyond prevention. Prophylaxis would be much more efficient if a biochemical marker of myocardiocyte damage could be reliably used to stop further chemotherapy at the correct time before irreversible progressive ‘macroscopic’ damage becomes evident upon imaging. Work is currently progressing to identify the role of markers such as troponins and natriuretic peptides in this regard.

Key Words: Chemotherapy • Anthracyclines • Cyclophosphamide • Cardiotoxicity • Cardiomyopathy • Heart

Received March 21, 2001; Revised July 17, 2001; Accepted September 19, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Cytotoxic antibiotics
 3. Alkylating agents
 4. Other chemotherapeutic agents
 References
 
Cardiotoxicity is a recognised chemotherapy-induced adverse event. As early as 1967, there were reports of heart failure in children treated with doxorubicin [1]. Since then the cytostatic antibiotics of the anthracycline class remain the most common cardiotoxic chemotherapeutic agents. There are, however, a number of other chemotherapeutic agents that cause cardiotoxicity which are not so well recognised by many clinicians.

Cardiac events associated with chemotherapy vary from mild transient blood pressure and/or electrocardiographic (ECG) changes to more serious arrhythmias, myocarditis, pericarditis, myocardial infarction and cardiomyopathy, which may end in left ventricular dysfunction (LVD) or congestive heart failure (CHF).

The aim of this article is to review the potentially serious cardiotoxicity of chemotherapeutic agents in current practice (with the exception of the hormonal agents and immune-modulators, e.g. Interferon) and to provide guidance — where evidence exists — as how to minimise, and ideally prevent, such serious side effects.


   2. Cytotoxic antibiotics
Top
 Abstract
 1. Introduction
 2. Cytotoxic antibiotics
3. Alkylating agents
 4. Other chemotherapeutic agents
 References
 
2.1. Anthracyclines
The cytotoxic antibiotics daunorubicin and doxorubicin are isolated form fungi belonging to the species Streptomyces. They demonstrated a clear dose-response relationship in several curative chemotherapeutic regimens [2,3]. Cardiotoxicity of such agents, however, necessitates dose reduction that might reduce remission rates and survival.

2.2. Mitoxtantrone
This non-cell-cycle-specific anthraquinone derivative was developed to provide broad-spectrum anti-tumour activity, similar to anthracyclines, without cardiotoxicity. Although initial animal studies revealed a lack of cardiotoxicity [64,65], mitoxantrone cardiotoxicity soon became evident in clinical trials. It has been shown to have an anthracycline-like spectrum of cardiotoxicity. Prior doxorubicin therapy and mitoxantrone cumulative dose are the main risk factors [66]. The incidence of CHF significantly increases (>5%) beyond a cumulative dose of 160 mg/m2, even in absence of previous doxorubicin exposure [67].

Two distinct subtypes of anthracycline-induced cardiotoxicity have been described, acute/subacute cardiotoxicity and chronic progressive cardiotoxicity.

2.2.1. Acute/subacute cardiotoxicity
This form of cardiotoxicity may occur within a week of the treatment. It may occur after a single dose of the agent but is rarely of serious clinical consequences. Transient electrophysiologic abnormalities detected as ECG changes may be seen in 20–30% of the patients as non-specific ST and T wave changes, T wave flattening, decreased QRS voltage and/or prolongation of the QT interval. Arrhythmias, including ventricular, supraventricular and junctional tachycardias are seen in 0.5–3% of patients with overall incidence of 0.7% [4]. More serious arrhythmias, such as atrial flutter or atrial fibrillation, are rare. Subacute cardiotoxicity has resulted in acute left ventricular failure, pericarditis or a fatal pericarditis-myocarditis syndrome in some rare cases [5]. The ECG changes or arrhythmias do not appear to be related to the chronic cardiomyopathy [6].

2.2.2. Chronic progressive cardiotoxicity
This is the more recognised and clinically significant subtype of cardiotoxicity. Chronic anthracycline-induced cardiomyopathy can present as an early onset [7], within a year of the treatment, or progress slowly to become manifest only years to decades after chemotherapy completion. It is therefore traditional to subdivide this subtype into two distinct entities, early and late onset cardiotoxicity [6,8], using the arbitrary time point of one year after completion of anthracycline treatment. This originated from the work of Von Hoff et al. [7] who reported that heart failure due to anthracycline cardiomyopathy occurred 0–231 days after the completion therapy. This was a retrospective analysis of 4018 patient's records with the end point being clinically manifest congestive heart failure as recorded by the treating clinician (65 patients excluded from the analysis due to insufficient information on the post-doxorubicin therapy cardiac status). In reality, however, cardiotoxicity appears to occur along a continuum of time. Steinherz et al. have shown that both the incidence and severity of systolic ventricular dysfunction increases with the length of follow up [9]. The incidence of such a complication is therefore reported variably by different groups, depending on the anthracycline cumulative dose, the presence of other risk factors, (e.g. mediastinal irradiation), the length of follow-up, parameters used for the assessment and the end-points measured. An incidence as high as 65% of increased afterload and/or decreased contractility has been reported with cumulative doxorubicin doses of as low as 228 mg/m2 in patients with leukaemia up to 15 years after treatment [10]. The incidence of symptomatic heart failure during or within the first year of completing anthracycline therapy is <3% [7,9,11]. Early onset cardiotoxicity (occurring during or within one year of anthracycline therapy), is the largest predictor of the development of late onset cardiotoxicity [9,10,12,13].

2.2.3. Risk factors
Chronic progressive cardiotoxicity appear to be related to certain risk factors. These include cumulative dose [7,9,10], rate of administration [7,14–19], female gender [12,20], both younger and older age [7,10,12,19], pre-existing heart disease and hypertension [7] and mediastinal irradiation [21–23]. Although unalterable, the time interval since anthracycline chemotherapy should also be considered as a risk factor particularly in those who received the drug in their childhood [9,10,12,13].

The incidence of CHF secondary to doxorubicin-induced cardiomyopathy depends on the cumulative dose of the drug [7]. At a cumulative dose of <400 mg/m2 the incidence of CHF — occurring 0–231 days after the completion of anthracycline therapy — was 0.14%. This increased to 7% at a dose of 550 mg/m2 and to 18% at a dose of 700 mg/m2 [7]. This rapid increase in the clinical cardiotoxicity at doses >550 mg/m2 has made this the empirical maximum cumulative dose to minimise doxorubicin-induced heart failure. There is a great individual variability in the tolerable anthracycline dose, both in adults and children. Five patients in the Von Hoff's series (3941 patients) received >1000 mg/m2, none of them sustained clinically manifest CHF [7]. A cumulative dose of anthracycline that does not result in cardiotoxicity has not been established [13].

Anthracycline-induced cardiotoxicity has been associated with the peak plasma drug concentration. The anti-neoplastic activity is, however, proportional to the total systemic exposure or the tissue concentration over time rather than the peak plasma concentration [14]. There is an evidence that doxorubicin becomes less cardiotoxic when administered as a prolonged, continuous intravenous infusion over more than 48–96 h [14]. Beyond 50 mg/m2 dose per day, there appears to be 2.81 times greater risk [19]. This is probably why anthracycline regimens given as weekly injections instead of a single bolus injection every 3 weeks were found less cardiotoxic [15–18].

Children appear to be at higher risk of developing anthracycline-induced cardiotoxicity [10,12,19]. An age of <4 years at the time of exposure has been shown to be a significant risk factor. It was mainly predictive of increased afterload due to reduced ventricular wall thickness [10]. Anthracyclines have been shown to alter transcription of myocellular proteins [24]. The inappropriate reduction in the left ventricular wall thickness found in children previously treated with anthracyclines [10,13] could be the result of such an effect.

In adults, an increasing risk of doxorubicin-induced CHF with increasing patient age has been observed (P=0.0027) [7]. Previous cardiac disease and hypertension may also potentially increase the risk of doxorubicin-induced CHF (P=0.08) [7].

Female patients appear to be more vulnerable to the cardiotoxic effects of anthracyclines [12,20].

Radiotherapy is frequently used in combination with multidrug chemotherapy protocols in patients with various haematological and solid neoplasms. Mediastinal irradiation is believed to increase anthracycline-induced cardiotoxicity [21–23]. Severity of histopathological changes was significantly higher (P<0.01) in patients pre-treated with mediastinal irradiation [22].

A recently published study on a cohort of 607 children with long-term follow-up (mean 6.3 years) has shown the only independent risk factor is a cumulative dose of >300 mg/m2. The other possible risk factors, (i.e. female sex, younger age at diagnosis, radiotherapy involving the heart and ifosfamide or cyclophosphamide treatment) were not associated with increased risk in this cohort [25].

2.2.4. Prophylaxis
Chronic cardiotoxicity limits the use of these efficient anti-neoplastic agents. Measures, which could prevent cardiotoxicity — or at least minimise it — while maintaining their anti-neoplastic efficacy would be of interest. This can be achieved by:

  • identifying risk factors prior to commencing anthracycline chemotherapy to modify the dose and/or the administration rate and schedule, and to identify patients in whom anthracyclines should be avoided altogether;
  • careful regular monitoring of the patients during and following completion of anthracycline therapy;
  • use of anthracycline analogues of comparable efficacy and less cardiotoxicity whenever possible; and
  • use of cardioprotective drugs when indicated.

Identifying patients at risk of cardiotoxicity is the first and crucial step for prophylaxis. The difficulty starts as early as this for two main reasons; firstly, as mentioned earlier, there appears to be a great variation in the individual sensitivity to anthracyclines. Histopathologic changes consistent with anthracycline-induced cardiotoxicity have been noted at doses as low as 183 mg/m2 (less than one-third of what is considered conventional maximum cumulative dose) [26], while doses of >1000 mg/m2 been tolerated by others [7,27]. Secondly, there is no ideal monitoring test for prediction of late onset cardiotoxicity.

In practice, monitoring still depends on signs of early (subclinical) reduction of left ventricular systolic function aiming at early discontinuation of anthracyclines.

Non-invasive echocardiographic measurement of left ventricular ejection fraction (LVEF) and fractional shorting (FS) is by far the most commonly used in most centres. Complete recovery of echocardiographic LVEF and FS may occur if anthracycline therapy is discontinued at an early stage [28], although this does not necessarily exclude long-term reductions in functional reserve [29]. Radionuclide angiocardiography is also widely used in monitoring for early anthracycline-induced cardiotoxicity. Schwartz and associates, proposed guidelines for prophylaxis against anthracycline-induced heart failure based on serial radionuclide measurement of LVEF [30]. Patients with a baseline LVEF of ≤30% should not receive anthracycline therapy. Those with LVEF of 30–50% can receive doxorubicin, but measures should be repeated before each dose. For patients with LVEF ≥50%, evaluations should be repeated after a cumulative dose of 250-300 mg/m2 and thereafter at 450 mg/m2 if they have no risk factors. Doxorubicin therapy should be stopped if there is a ≥10% absolute drop in the EF with a drop of the LVEF to ≤50% in patients with baseline LVEF ≥50%, and to ≤30% in those with a baseline LVEF of 30–50%. Multivariate analysis demonstrated a fourfold reduction in the incidence of CHF in those patients whose management was concordant with the proposed guideline criteria [30]. Unfortunately, resting LVEF obtained by radionuclide angiocardiography is relatively insensitive in detecting early anthracycline cardiotoxicity. Both LVEF and FS are load-dependant indices, which give an estimate of the overall left ventricular systolic performance rather than the absolute contractility. Sensitivity could be increased by using load-independent contractility indices, e.g.stress velocity index. Exercise radionuclide studies may also increase the chance of detecting subclinical anthracycline-induced cardiotoxicity [21,31]. Failure to increase the ejection fraction by 5% over the resting value has been suggested to be a marker of high risk for developing anthracycline-induced ventricular dysfunction [32]. Serial testing is, however, required to improve the low specificity of a single test and maximal exercise is often difficult for patients receiving chemotherapy, most of them are debilitated.

Measuring diastolic parameters has been found useful in early detection of anthracycline-induced cardiomyopathy. Results are still inconsistent, though, regarding whether this precedes detectable systolic dysfunction [33–40]. This probably reflects the fact that in some patients anthracyclines cause extensive endocardial fibrous thickening, which gives restrictive cardiomyopathic picture [41].

Endomyocardial biopsy is a fairly sensitive indicator of chronic anthracycline-induced cardiotoxicity. A semi-quantitative histological scoring system that correlated well with the cumulative anthracycline dose has been available since 1984 [42]. Such a monitoring strategy did not find its way to clinical practice for clear reasons; being invasive with concerns about safety of its repetition, particularly in children [43]. Moreover, underestimation of cardiac damage with right ventricular biopsy may occur because of scattered cardiomyopathic changes [44] or the predominance of left ventricular injury [41]. Finally, expertise in obtaining and interpreting biopsy specimens is not widely available.

2.2.5. Prospects
The ideal screening and monitoring technique is not available yet. This might depend on detection of susceptible genotype(s), by one of the recent molecular techniques, and/or a biochemical marker. The former might explain the great individual tolerability variation and define individual in whom anthracyclines should be avoided. The latter on the other hand aims at reliable prediction of irreversible myocardioctye damage in a way much like the pattern of liver enzymes many years before the cirrhosis in chronic active hepatitis. Natriuretic peptides could be useful in this regards as shown by preliminary studies [45–48]. The studies are, however, of small size and of short-term follow up. A recent study, however, suggested that serial natriuretic peptide measurements can not be used in predicting the impairment of left ventricular function. They found that 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 [49]

Endothelin-1 could also be a potential predictor. In a single small-scale study so far, progressive elevation of its plasma levels occurred before deterioration of LVEF in patients who subsequently developed CHF [50,51]. Cardiac troponins also warrant further investigations to evaluate their potential use for monitoring patients on and post-anthracycline therapy [52,53].

2.2.6. Anthracycline semi-synthetic analogues
Epirubicin is an epimer of doxorubicin with a comparable anti-tumour activity and less cardiotoxicity [54–56]. Cardiotoxicity appears to occur at a higher cumulative dose of >900 mg/m2.

Idarubicin is a lipophilic semi-synthetic derivative of daunorubicin, that can be administered orally [6], was shown to be less cardiotoxic than doxorubicin [57,58].

2.2.7. Cardioprotective agents
Dexrazoxane is a derivative of ethylene-diamine tetraacytic acid (EDTA) that readily penetrates cell membranes and acts as an intracellular chelating agent [6]. Its proposed mechanism of cardioprotection is through the chelation of intracellular iron, which may decrease anthracycline-induced free radical generation. Dexrazoxane (ICRF-187) has been shown to decrease the incidence of clinical CHF in patients treated with anthracyclines [59,60]. Neither the normal anti-oxidant mechanisms nor the pharmacokinetics of doxorubicin or its metabolites are affected by dexrazoxane [61]. It is given via slow IV push or rapid infusion not more than 30 minutes before doxorubicin administration. The recommended dose is 10 times that of the scheduled doxorubicin dose. It is generally well tolerated, but side-effects include enhanced myelosuppression and pain on injection [60].

Concerns, however, exist as regards possible interference of dexrazoxane with the efficacy of the anthracycline anti-tumour effect [60,62]. It is, therefore, not routinely recommended with anthracycline therapy at least at the present time. Recent guidelines by the American Society of Clinical Oncology advised that dexrazoxane may only be considered for patients with metastatic breast cancer who have received a cumulative doxorubicin dose of ≥300 mg/m2 in the metastatic setting and who may benefit from further anthracycline therapy. Patients receiving dexrazoxane should continue to be monitored for anthracycline-induced cardiotoxicity [63].


   3. Alkylating agents
Top
 Abstract
 1. Introduction
 2. Cytotoxic antibiotics
 3. Alkylating agents
4. Other chemotherapeutic agents
 References
 
3.1. Cyclophosphamide
Cyclophosphamide is a non-cell-cycle-specific alkylating agent which is a mainstay of most pre-transplant conditioning regimens. High-dose cyclophosphamide can cause an acute form of cardiotoxicity within 10 days of its administration [68–70]. Cyclophosphamide-induced cardiotoxicity presents as a combination of symptoms and signs of myo-pericarditis, which could lead to fatal complications, (e.g. CHF, arrhythmias, cardiac tamponade) [68,70,71]. The total dose of cyclophosphamide per course is so far the only reproducible risk factor [69]. The incidence of symptomatic cyclophosphamide-induced cardiotoxicity in two series [71,72], when combined, was 22% (16/72) and of fatal cardiotoxicity was 11%. A total dose of >170–180 mg/kg per course (over 4–7 days) was the risk factor. Goldberg et al, found that doses based on body surface area — rather than body weight — correlate well with incidence of cyclophosphamide-induced cardiotoxicity [68]. The incidence of symptomatic cyclophosphamide-induced cardiotoxicity in a group of patients who never had prior anthracycline therapy was 25% (13/52) with 12% (6/52) mortality rate when the cyclophosphamide dose exceeded 1.55 mg/m2 per day. Those who received lower than 1.55 mg/m2 per day had 3% (1/32) symptomatic cardiotoxicity with no mortality [68]. The fact that young children have a relatively higher body surface area probably explains the lower incidence and severity of cyclophosphamide-induced cardiotoxicity in them compared to adolescents and adults [6,68]. Cyclophosphamide-induced cardiotoxicity may last from one to six days and despite the relatively high mortality rate there are no long-term sequels or late cardiotoxicity in patients who survive the initial acute event [71]. So far, there is no evidence of cumulative cyclophosphamide cardiotoxicity.

3.1.1. Prophylaxis
Ideal prophylaxis would depend on the avoidance of exceeding a certain critical dose, beyond which the incidence and severity of cardiotoxicity becomes unacceptably high. Identification of this critical dose warrants further large-scale studies, but it is likely to be approximately 1.55 g/m2 per day as shown by Goldberg et al. [73]. We recommend, therefore, that haematopoietic stem cell transplant protocols should be modified to use cyclophosphamide doses calculated per body surface area/day in order to limit the daily dose to <1.55 g/m2. The current evidence shows that this will significantly reduce this potentially fatal cardiotoxicity without affecting engraftment success [73].

Secondary prevention of cyclophosphamide-induced cardiotoxicity necessitates clinicians to be aware of this potential complication. They should keep it in mind when looking after patients who have received a high-dose of cyclophosphamide within the previous two weeks.

3.2. Ifosfamide
Ifosfamide, structurally similar to cyclophosphamide, seems to have a similar cardiotoxicity pattern with a 30% incidence of cardiotoxicity with doses beyond 20 g/m2 [74]. Further studies are needed to confirm the critical dose that should not be exceeded, as this will be the efficient route of prophylaxis.

3.3. Mitomycin
There is a strong evidence that mitomycin enhances doxorubicin-induced cardiomyopathy when administered in combination with or following such an agent [75,76]. MMC-related cardiotoxicity is dose-dependent, occurring at cumulative dose levels of 30 mg/m2, mainly in patients treated, previously or simultaneously, with doxorubicin [77]. Careful monitoring of left ventricular function is therefore essential as with anthracycline chemotherapy.


   4. Other chemotherapeutic agents
Top
 Abstract
 1. Introduction
 2. Cytotoxic antibiotics
 3. Alkylating agents
 4. Other chemotherapeutic agents
References
 
The above mentioned chemotherapeutic agents are the most significant as far as cardiotoxicity in clinical practice is concerned. The amount of literature available, as reflected in this article, shows their relative significance in this context. It is worth mentioning though that many other chemotherapeutic agents could sometimes cause transient cardiotoxicity such as transient ECG change, arrhythmias and/or blood pressure changes. Although these are rarely of clinical significance, clinicians should be aware of them.

Finally, fluorouracil (5-FU) should be mentioned. Care should be taken with this synthetic pyrimidine anti-metabolite as it can cause myocardial ischaemia [78]. Although rare (1.6%) it has to be taken into account in practice, particularly in those patients already affected with cardiac disease, as cases of massive myocardial infarctions have occurred [78–80]. 5-FU cardiotoxicity is more common following high dose continuous infusion than after IV bolus adminstration [81]. Prophylaxis starts with identifying those with ischaemic heart disease in whom the agent should be avoided. Using IV bolus administration rather than continuous administration is advisable based on the current available evidence. Taking this potential cardiotoxicity into account in practice should be of prophylactic benefit.


   References
Top
 Abstract
 1. Introduction
 2. Cytotoxic antibiotics
 3. Alkylating agents
 4. Other chemotherapeutic agents
 References
 

  1. Tan C., Tasaka H., Kou-Ping Y., et al. Daunomycin, an antitumor antibiotic, in the treatment of neoplastic disease: clinical evaluation with special reference to childhood leukemia. Cancer (1967) 20:333–353.[CrossRef][Web of Science][Medline]
  2. Hitchcock-Bryan S., Jeal G.R.C. The impact of induction anthracyclines on long-term failure-free survival in childhood acute lymphoblastic leukemia. Med Pediatr Oncol (1986) 14:211–215.[Web of Science][Medline]
  3. Ettinghausen S.E., Bonow R.O., Palmeri S.T., et al. Prospective study of cardiomyopathy induced by adjuvant doxorubicin therapy in patients with soft-tissue sarcomas. Arch Surg (1986) 121:1445–1451.[Abstract/Free Full Text]
  4. Frishman W.H., Sung H.M., Yee H.C., et al. Cardiovascular toxicity with cancer chemotherapy. Curr Probl Cancer (1997) 21:301–360.[CrossRef][Medline]
  5. Ferrans V.J. Overview of cardiac pathology in relation to anthracycline cardiotoxicity. Cancer Treat Rep (1978) 62:955–961.[Web of Science][Medline]
  6. Pai V.B., Nahata M.C. Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Saf (2000) 22:263–302.[CrossRef][Web of Science][Medline]
  7. VonHoff D.D., Layard M.W., Basa P., et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med (1979) 91:710–717.[Abstract/Free Full Text]
  8. Shan K., Lincoff A.M., Young J.B. Anthracycline-induced cardiotoxicity. Ann Intern Med (1996) 125:47–58.[Abstract/Free Full Text]
  9. Steinherz L.J., Steinherz P.G., Tan C.T., Heller G., Murphy M.L. Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA (1991) 266:1672–1677.[Abstract/Free Full Text]
  10. Lipshultz S.E., Colan S.D., Gelber R.D., Perez-Atayde A.R., Sallan S.E., Sanders S.P. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med (1991) 324:808–815.[Abstract]
  11. Bu'Lock F.A., Mott M.G., Oakhill A., Martin R.P. Left ventricular diastolic filling patterns associated with progressive anthracycline-induced myocardial damage: A prospective study. Pediatr Cardiol (1999) 20:252–263.[CrossRef][Web of Science][Medline]
  12. Lipshultz S.E., Lipsitz S.R., Mone S.M., et al. Female sex and drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med (1995) 332:1738–1743.[Abstract/Free Full Text]
  13. Grenier M.A., Lipshultz S.E. Epidemiology of anthracycline cardiotoxicity in children and adults. Semin Oncol (1998) 25:72–85.[Web of Science][Medline]
  14. Legha S.S., Benjamin R.S., Mackay B., et al. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med (1982) 96:133–139.[Abstract/Free Full Text]
  15. Torti F.M., Bristow M.R., Howes A.E., et al. Reduced cardiotoxicity of doxorubicin delivered on a weekly schedule. Assessment by endomyocardial biopsy. Ann Intern Med (1983) 99:745–749.[Abstract/Free Full Text]
  16. Weiss A.J., Metter G.E., Fletcher W.S., Wilson W.L., Grage T.B., Ramirez G. Studies on adriamycin using a weekly regimen demonstrating its clinical effectiveness and lack of cardiac toxicity. Cancer Treat Rep (1976) 60:813–822.[Web of Science][Medline]
  17. Weiss A.J., Manthel R.W. Experience with the use of adriamycin in combination with other anticancer agents using a weekly schedule, with particular reference to lack of cardiac toxicity. Cancer (1977) 40:2046–2052.[CrossRef][Web of Science][Medline]
  18. Chlebowski R.T., Paroly W.S., Pugh R.P., et al. Adriamycin given as a weekly schedule without a loading course: clinically effective with reduced incidence of cardiotoxicity. Cancer Treat Rep (1980) 64:47–51.[Web of Science][Medline]
  19. Krischer J.P., Epstein S., Cuthbertson D.D., Goorin A.M., Epstein M.L., Lipshultz S.E. Clinical cardiotoxicity following anthracycline treatment for childhood cancer: the Pediatric Oncology Group experience. J Clin Oncol (1997) 15:1544–1552.[Abstract]
  20. Silber J.H., Jakacki R.I., Larsen R.L., Goldwein J.W., Barber G. Increased risk of cardiac dysfunction after anthracyclines in girls. Med Pediatr Oncol (1993) 21:477–479.[Web of Science][Medline]
  21. Bristow M.R., Mason J.W., Billingham M.E., Daniels J.R. Doxorubicin cardiomyopathy: evaluation by phonocardiography, endomyocardial biopsy, and cardiac catheterization. Ann Intern Med (1978) 88:168–175.[Abstract/Free Full Text]
  22. Praga C., Beretta G., Vigo P.L., et al. Adriamycin cardiotoxicity: a survey of 1273 patients. Cancer Treat Rep (1979) 63:827–834.[Web of Science][Medline]
  23. Pihkala J., Saarinen U.M., Lundstrom U., et al. Myocardial function in children and adolescents after therapy with anthracyclines and chest irradiation. Eur J Cancer (1996) 32A:97–103.[CrossRef]
  24. Boucek R.J., Miracle A., Anderson M., Engelman R., Atkinson J., Dodd D.A. Persistent effects of doxorubicin on cardiac gene expression. J Mol Cell Cardiol (1999) 31:1435–1446.[CrossRef][Web of Science][Medline]
  25. Kremer L.C., van Dalen E.C., Offringa M., Ottenkamp J., Voute P.A. Anthracycline-Induced Clinical Heart Failure in a Cohort of 607 Children: Long-Term Follow-Up Study. J Clin Oncol (2001) 19:191–196.[Abstract/Free Full Text]
  26. Friedman M.A., Bozdech M.J., Billingham M.E., Rider A.K. Doxorubicin cardiotoxicity. Serial endomyocardial biopsies and systolic time intervals. JAMA (1978) 240:1603–1606.[Abstract/Free Full Text]
  27. Bristow M.R., Thompson P.D., Martin R.P., Mason J.W., Billingham M.E., Harrison D.C. Early anthracycline cardiotoxicity. Am J Med (1978) 65:823–832.[CrossRef][Web of Science][Medline]
  28. Lewis A.B., Crouse V.L., Evans W., Takahashi M., Siegel S.E. Recovery of left ventricular function following discontinuation of anthracycline chemotherapy in children. Pediatrics (1981) 68:67–72.[Abstract/Free Full Text]
  29. Moreb J.S., Oblon D.J. Outcome of clinical congestive heart failure induced by anthracycline chemotherapy. Cancer (1992) 70:2637–2641.[CrossRef][Web of Science][Medline]
  30. Schwartz R.G., McKenzie W.B., Alexander J., et al. Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy. Seven-year experience using serial radionuclide angiocardiography. Am J Med (1987) 82:1109–1118.[CrossRef][Web of Science][Medline]
  31. Bristow M.R., Mason J.W., Billingham M.E., Daniels J.R. Dose-effect and structure-function relationships in doxorubicin cardiomyopathy. Am Heart J (1981) 102:709–718.[CrossRef][Web of Science][Medline]
  32. McKillop J.H., Bristow M.R., Goris M.L., Billingham M.E., Bockemuehl K. Sensitivity and specificity of radionuclide ejection fractions in doxorubicin cardiotoxicity. Am Heart J (1983) 106:1048–1056.[CrossRef][Web of Science][Medline]
  33. Lee B.H., Goodenday L.S., Muswick G.J., Yasnoff W.A., Leighton R.F., Skeel R.T. Alterations in left ventricular diastolic function with doxorubicin therapy. J Am Coll Cardiol (1987) 9:184–188.[Abstract]
  34. Hausdorf G., Morf G., Beron G., et al. Long term doxorubicin cardiotoxicity in childhood: non-invasive evaluation of the contractile state and diastolic filling. Br Heart J (1988) 60:309–315.[Abstract/Free Full Text]
  35. Marchandise B., Schroeder E., Bosly A., et al. Early detection of doxorubicin cardiotoxicity: interest of Doppler echocardiographic analysis of left ventricular filling dynamics. Am Heart J (1989) 118:92–98.[CrossRef][Web of Science][Medline]
  36. Stoddard M.F., Seeger J., Liddell N.E., Hadley T.J., Sullivan D.M., Kupersmith J. Prolongation of isovolumetric relaxation time as assessed by Doppler echocardiography predicts doxorubicin-induced systolic dysfunction in humans. J Am Coll Cardiol (1992) 20:62–69.[Abstract]
  37. Ganz W.I., Sridhar K.S., Forness T.J. Detection of early anthracycline cardiotoxicity by monitoring the peak filling rate. Am J Clin Oncol (1993) 16:109–112.[Web of Science][Medline]
  38. Ewer M.S., Ali M.K., Gibbs H.R., et al. Cardiac diastolic function in pediatric patients receiving doxorubicin. Acta Oncol (1994) 33:645–649.[Web of Science][Medline]
  39. Cottin Y., Touzery C., Coudert B., et al. Impairment of diastolic function during short-term anthracycline chemotherapy. Br Heart J (1995) 73:61–64.[Abstract/Free Full Text]
  40. Schmitt K., Tulzer G., Merl M., et al. Early detection of doxorubicin and daunorubicin cardiotoxicity by echocardiography: diastolic versus systolic parameters. Eur J Pediatr (1995) 154:201–204.[CrossRef][Web of Science][Medline]
  41. Mortensen S.A., Olsen H.S., Baandrup U. Chronic anthracycline cardiotoxicity: haemodynamic and histopathological manifestations suggesting a restrictive endomyocardial disease. Br Heart J (1986) 55:274–282.[Abstract/Free Full Text]
  42. Billingham M.E.B.M. Evaluation of anthracycline cardiotoxicity:predictive ability and functional correlation of endomyocardial biopsy. Cancer Treat Symp (1984) 3:71–76.
  43. Pegelow C.H., Popper R.W., de Wit S.A., King O.Y., Wilbur J.R.:. Endomyocardial biopsy to monitor anthracycline therapy in children. J Clin Oncol (1984) 2:443–446.[Abstract]
  44. Isner J.M., Ferrans V.J., Cohen S.R., et al. Clinical and morphologic cardiac findings after anthracycline chemotherapy. Analysis of 64 patients studied at necropsy. Am J Cardiol (1983) 51:1167–1174.[CrossRef][Web of Science][Medline]
  45. Neri B., DeScalzi M., De L.V., Gemelli M.T., Ghezzi P., Pacini P. Preliminary study on behaviour of atrial natriuretic factor in anthracycline-related cardiac toxicity. Int J Clin Pharmacol Res (1991) 11:75–81.[Web of Science][Medline]
  46. Bauch M., Ester A., Kimura B., Victorica B.E., Kedar A., Phillips M.I. Atrial natriuretic peptide as a marker for doxorubicin-induced cardiotoxic effects. Cancer (1992) 69:1492–1497.[CrossRef][Web of Science][Medline]
  47. Tikanoja T., Riikonen P., Perkkio M., Helenius T. Serum N-terminal atrial natriuretic peptide (NT-ANP) in the cardiac follow-up in children with cancer. Med Pediatr Oncol (1998) 31:73–78.[CrossRef][Web of Science][Medline]
  48. Suzuki T., Hayashi D., Yamazaki T., et al. Elevated B-type natriuretic peptide levels after anthracycline administration. Am Heart J (1998) 136:362–363.[CrossRef][Web of Science][Medline]
  49. Nousiainen T., Jantunen E., Vanninen E., Remes J., Vuolteenaho O., Hartikainen J. Natriuretic peptides as markers of cardiotoxicity during doxorubicin treatment for non-Hodgkin's lymphoma. Eur J Haematol (1999) 62:135–141.[Web of Science][Medline]
  50. Yamashita J., Ogawa M., Nomura K. Plasma endothelin-1 and doxorubicin cardiotoxicity. N Engl J Med (1994) 331:1528–1529.[Free Full Text]
  51. Yamashita J., Ogawa M., Shirakusa T. Plasma endothelin-1 as a marker for doxorubicin cardiotoxicity. Int J Cancer (1995) 62:542–547.[Web of Science][Medline]
  52. Lipshultz S.E., Rifai N., Sallan S.E., et al. Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation (1997) 96:2641–2648.[Abstract/Free Full Text]
  53. Missov E., Calzolari C., Davy J.M., Leclercq F., Rossi M., Pau B. Cardiac troponin I in patients with hematologic malignancies. Coron Artery Dis (1997) 8:537–541.[Web of Science][Medline]
  54. Ganzina F. 4'-epi-doxorubicin, a new analogue of doxorubicin: a preliminary overview of preclinical and clinical data. Cancer Treat Rev (1983) 10:1–22.[Web of Science][Medline]
  55. Jain K.K., Casper E.S., Geller N.L., et al. A prospective randomized comparison of epirubicin and doxorubicin in patients with advanced breast cancer. J Clin Oncol (1985) 3:818–826.[Abstract/Free Full Text]
  56. Brambilla C., Rossi A., Bonfante V., et al. Phase II study of doxorubicin versus epirubicin in advanced breast cancer. Cancer Treat Rep (1986) 70:261–266.[Web of Science][Medline]
  57. Villani F., Galimberti M., Comazzi R., Crippa F. Evaluation of cardiac toxicity of idarubicin (4-demethoxydaunorubicin). Eur J Cancer Clin Oncol (1989) 25:13–18.[CrossRef][Web of Science][Medline]
  58. Lopez M., Contegiacomo A., Vici P., et al. A prospective randomized trial of doxorubicin versus idarubicin in the treatment of advanced breast cancer. Cancer (1989) 64:2431–2436.[CrossRef][Web of Science][Medline]
  59. Speyer J.L., Green M.D., Kramer E., et al. Protective effect of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer. N Engl J Med (1988) 319:745–752.[Abstract]
  60. Speyer J.L., Green M.D., Zeleniuch-Jacquotte A., et al. ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. J Clin Oncol (1992) 10:117–127.[Web of Science][Medline]
  61. Hochster H., Liebes L., Wadler S., et al. Pharmacokinetics of the cardioprotector ADR-529 (ICRF-187) in escalating doses combined with fixed-dose doxorubicin. J Natl Cancer Inst (1992) 84:1725–1730.[Abstract/Free Full Text]
  62. Swain S.M., Whaley F.S., Gerber M.C., et al. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol (1997) 15:1318–1332.[Abstract/Free Full Text]
  63. Hensley M.L., Schuchter L.M., Lindley C., et al. American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants. J Clin Oncol (1999) 17:3333–3355.[Abstract/Free Full Text]
  64. Henderson B.M., Dougherty W.J., James V.C., Tilley L.P., Noble J.F. Safety assessment of a new anticancer compound, mitoxantrone in beagle dogs: comparison with doxorubicin.; I. Clinical observations. Cancer Treat Rep (1982) 66:1139–1143.[Web of Science][Medline]
  65. Sparano B.M., Gordon G., Hall C., Iatropoulos M.J., Noble J.F. Safety assessment of new anticancer compound, mitoxantrone, in beagle dogs: comparison with doxorubicin. II. Histologic and ultrastructural pathology. Cancer Treat Rep (1982) 66:1145–1158.[Web of Science][Medline]
  66. Mather F.J., Simon R.M., Clark G.M., Von Hoff D.D. Cardiotoxicity in patients treated with mitoxantrone: Southwest Oncology Group phase II studies. Cancer Treat Rep (1987) 71:609–613.[Web of Science][Medline]
  67. Posner L.E., Dukart G., Goldberg J., Bernstein T., Cartwright K. Mitoxantrone: an overview of safety and toxicity. Invest New Drugs (1985) 3:123–132.[Web of Science][Medline]
  68. Goldberg M.A., Antin J.H., Guinan E.C., Rappeport J.M. Cyclophosphamide cardiotoxicity: an analysis of dosing as a risk factor. Blood (1986) 68:1114–1118.[Abstract/Free Full Text]
  69. Dow E., Schulman H., Agura E. Cyclophosphamide cardiac injury mimicking acute myocardial infarction. Bone Marrow Transplant (1993) 12:169–172.[Web of Science][Medline]
  70. Gardner S.F., Lazarus H.M., Bednarczyk E.M., et al. High-dose cyclophosphamide-induced myocardial damage during BMT: assessment by positron emission tomography. Bone Marrow Transplant (1993) 12:139–144.[Web of Science][Medline]
  71. Gottdiener J.S., Appelbaum F.R., Ferrans V.J., Deisseroth A., Ziegler J. Cardiotoxicity associated with high-dose cyclophosphamide therapy. Arch Intern Med (1981) 141:758–763.[Abstract/Free Full Text]
  72. Steinherz L.J., Steinherz P.G., Mangiacasale D., et al. Cardiac changes with cyclophosphamide. Med Pediatr Oncol (1981) 9:417–422.[Web of Science][Medline]
  73. Goldberg M.A., Antin J.H., Guinan E.C., Rappeport J.M. Cyclophosphamide cardiotoxicity: an analysis of dosing as a risk factor. Blood (1986) 68:1114–1118.[Abstract/Free Full Text]
  74. Quezado Z.M., Wilson W.H., Cunnion R.E., et al. High-dose ifosfamide is associated with severe, reversible cardiac dysfunction. Ann Intern Med (1993) 118:31–36.[Abstract/Free Full Text]
  75. Buzdar A.U., Legha S.S., Tashima C.K., et al. Adriamycin and mitomycin C: possible synergistic cardiotoxicity. Cancer Treat Rep (1978) 62:1005–1008.[Web of Science][Medline]
  76. Villani F., Comazzi R., Lacaita G., et al. Possible enhancement of the cardiotoxicity of doxorubicin when combined with mitomycin C. Med Oncol Tumor Pharmacother (1985) 2:93–97.[Web of Science][Medline]
  77. Verweij J., Funke-Kupper A.J., Teule G.J., Pinedo H.M. A prospective study on the dose dependency of cardiotoxicity induced by mitomycin C. Med Oncol Tumor Pharmacother (1988) 5:159–163.[Web of Science][Medline]
  78. Labianca R., Beretta G., Clerici M., Fraschini P., Luporini G. Cardiac toxicity of 5-fluorouracil: a study on 1083 patients. Tumori (1982) 68:505–510.[Web of Science][Medline]
  79. Patel B., Kloner R.A., Ensley J., Al Sarraf M., Kish J., Wynne J. 5-Fluorouracil cardiotoxicity: left ventricular dysfunction and effect of coronary vasodilators. Am J Med Sci (1987) 294:238–243.[Web of Science][Medline]
  80. Rezkalla S., Kloner R.A., Ensley J., et al. Continuous ambulatory ECG monitoring during fluorouracil therapy: a prospective study. J Clin Oncol (1989) 7:509–514.[Abstract]
  81. De Forni M., Malet-Martino M.C., Jaillais P., et al. Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study. J Clin Oncol (1992) 10:1795–1801.[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J Am Coll CardiolHome page
E. T.H. Yeh and C. L. Bickford
Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management.
J. Am. Coll. Cardiol., June 16, 2009; 53(24): 2231 - 2247.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
S. H. Armenian, C.-L. Sun, L. Francisco, J. Steinberger, S. Kurian, F. L. Wong, J. Sharp, R. Sposto, S. J. Forman, and S. Bhatia
Late Congestive Heart Failure After Hematopoietic Cell Transplantation
J. Clin. Oncol., December 1, 2008; 26(34): 5537 - 5543.
[Abstract] [Full Text] [PDF]

Home page
 Am J Health Syst PharmHome page
A. Georgy, J. Neceskas, and S. Goodin
Antiemetic care for patients with breast cancer: Focus on drug interactions and safety concerns
Am. J. Health Syst. Pharm., November 1, 2007; 64(21): 2227 - 2236.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
D. Cardinale, A. Colombo, M. T. Sandri, G. Lamantia, N. Colombo, M. Civelli, G. Martinelli, F. Veglia, C. Fiorentini, and C. M. Cipolla
Prevention of High-Dose Chemotherapy-Induced Cardiotoxicity in High-Risk Patients by Angiotensin-Converting Enzyme Inhibition
Circulation, December 5, 2006; 114(23): 2474 - 2481.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
L. Wojnowski, B. Kulle, M. Schirmer, G. Schluter, A. Schmidt, A. Rosenberger, S. Vonhof, H. Bickeboller, M. R. Toliat, E.-K. Suk, et al.
NAD(P)H Oxidase and Multidrug Resistance Protein Genetic Polymorphisms Are Associated With Doxorubicin-Induced Cardiotoxicity
Circulation, December 13, 2005; 112(24): 3754 - 3762.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
D. Cardinale, M. T. Sandri, A. Colombo, N. Colombo, M. Boeri, G. Lamantia, M. Civelli, F. Peccatori, G. Martinelli, C. Fiorentini, et al.
Prognostic Value of Troponin I in Cardiac Risk Stratification of Cancer Patients Undergoing High-Dose Chemotherapy
Circulation, June 8, 2004; 109(22): 2749 - 2754.
[Abstract] [Full Text] [PDF]

Home page
 Eur J Heart FailHome page
T. Simunek, I. Klimtova, J. Kaplanova, Y. Mazurova, M. Adamcova, M. Sterba, R. Hrdina, and V. Gersl
Rabbit model for in vivo study of anthracycline-induced heart failure and for the evaluation of protective agents
Eur J Heart Fail, June 1, 2004; 6(4): 377 - 387.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
E. A. Perez and R. Rodeheffer
Clinical Cardiac Tolerability of Trastuzumab
J. Clin. Oncol., January 15, 2004; 22(2): 322 - 329.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
L. E. Olson, D. Bedja, S. J. Alvey, A. J. Cardounel, K. L. Gabrielson, and R. H. Reeves
Protection from Doxorubicin-Induced Cardiac Toxicity in Mice with a Null Allele of Carbonyl Reductase 1
Cancer Res., October 15, 2003; 63(20): 6602 - 6606.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Gharib, M.I.
Right arrow Articles by Burnett, A.K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gharib, M.I.
Right arrow Articles by Burnett, A.K.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?