Cardiac Toxicity 4 to 20 Years After Completing Anthracycline Therapy

Steinherz, Laurel J.

doi:10.1001/jama.1991.03470120074036

Cited by 820 publications

(347 citation statements)

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“…This result was suggested in some studies (Steinherz et al, 1991(Steinherz et al, , 1993(Steinherz et al, , 1995, where radiotherapy (RT) vs no RT was studied. A total of 120 patients investigated had received radiotherapy, at some site in the body.…”

Section: Discussionmentioning

confidence: 72%

“…The late cardiac events among long-term childhood leukaemia and cancer survivors were first described in 1991 (Lipshultz et al, 1991;Steinherz et al, 1991Steinherz et al, , 1993, then later confirmed by many other teams. It was hypothesised that the loss of myocytes during anthracycline therapy might impair myocardial growth and lead to a gradual increase in left ventricular afterload and sometimes reduced contractility (Lipshultz et al, 1991(Lipshultz et al, , 1995Grenier and Lipshultz, 1998).…”

mentioning

confidence: 93%

“…It was hypothesised that the loss of myocytes during anthracycline therapy might impair myocardial growth and lead to a gradual increase in left ventricular afterload and sometimes reduced contractility (Lipshultz et al, 1991(Lipshultz et al, , 1995Grenier and Lipshultz, 1998). An increased risk was found to be associated with mediastinal radiotherapy and the time since drug administration (Steinherz et al, 1991(Steinherz et al, , 1993: the role of pregnancy, delivery, and weight-lifting activities in revealing cardiac deficits (Steinherz et al, 1993(Steinherz et al, , 1995 was highlighted. The frequency of cardiac abnormalities according to the anthracycline dose has been correlated with age at treatment, the time elapsed since treatment, and sex (Lipshultz et al, 1995;Silber et al, 1993;Steinherz et al, 1995).…”

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confidence: 99%

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Cardiac abnormalities 15 years and more after adriamycin therapy in 229 childhood survivors of a solid tumour at the Institut Gustave Roussy

et al. 2004

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The purpose of this paper was to determine the cardiac status in children 15 years or more after adriamycin therapy for a solid tumour. Of the 447 pts, 229 pts were fully studied and 218 were not. The following cardiac evaluations were proposed to all the 447 consecutive patients (pts): (1) cardiac Doppler US by one of two expert cardiologists; (2) cardiac rhythm and conduction abnormalities including 24-hour holter ECG; (3) 131 l-mlBG myocardial scintigraphy; (4) serum brain natriuretic peptide levels at rest; (5) an exercise test with VO 2 max measurement. The radiation doses delivered to 6 points in the heart were estimated for all patients who had received radiotherapy. Congestive heart failure was diagnosed in 24 of 229 (10%) evaluated pts, with a median interval of 15 years (0.3 -24 years) from the first symptom after adriamycin treatment. Among the 205 remaining pts, 13 asymptomatic pts (6%) had severe (n ¼ 4) (FSo20%) or marked (n ¼ 9) (20pFSo25%) systolic dysfunction. In the 192 others, the median meridional end-systolic wall stress was 91 (53 -135) and it exceeded 100 g cm À2 in 52 pts. Using a Cox model, only the cumulative dose of adriamycin and the average radiation dose to the heart, were identified as risk factors for a pathological cardiac status. In conclusion, the risk of cardiac failure or severe abnormalities increases with adriamycin treatment, radiotherapy and time since treatment, even after a follow-up of 15 years or more. In our series, after an average follow-up of 18 years, 39% of the children had a severe cardiac dysfunction or major ventricular overload conditions. The risk increases with the dose of adriamycin and radiation received to the heart, without evidence for threshold.

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Section: Discussionmentioning

confidence: 72%

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confidence: 93%

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Cardiac abnormalities 15 years and more after adriamycin therapy in 229 childhood survivors of a solid tumour at the Institut Gustave Roussy

et al. 2004

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“…Treatment with DOX is limited by a dose-dependent cardiotoxicity, which may lead to late side effects resulting in severe morbidity and mortality (Steinherz et al, 2001;Lipshultz et al, 2005). Although the 5-year survival of childhood cancer has improved from 30 to 70% in the last 40 years, the risk of death from cardiac events in these survivors is eight times higher than that in the normal population (Wouters et al, 2005).…”

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confidence: 99%

The effect of monohydroxyethylrutoside on doxorubicin-induced cardiotoxicity in patients treated for metastatic cancer in a phase II study

et al. 2007

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The purpose of this study was to investigate the cardioprotective effect of the semisynthetic flavonoid 7-monohydroxyethylrutoside (monoHER) on doxorubicin (DOX)-induced cardiotoxicity in a phase II study in patients with metastatic cancer. Eight patients with metastatic cancer were treated with DOX preceded by a 10 min i.v. infusion of 1500 mg m À2 monoHER. Five patients were examined by endomyocardial biopsy after reaching a cumulative dose of 300 mg m À2 . Histopathological changes in the cardiomyocytes (Billingham score) were compared with those described in literature for patients treated with DOX only. The mean biopsy score of the patients was higher (2.7) than the mean score (1.4) of historical data of patients who received similar cumulative doses of DOX. Although there is a considerable variability in few investigated patients, it was indicative that monoHER enhanced DOX-induced cardiotoxicity. However, the antitumour activity of DOX seemed better than expected: three of the four patients with metastatic soft-tissue sarcoma had a partial remission and the fourth patient stable disease. It is likely that the relatively high dose of monoHER is responsible for the lack of cardioprotection and for the high response rate in patients with soft-tissue sarcoma possibly by depleting the glutathione defense system in both heart and tumour.

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“…The risk of cardiomyopathy is dose-limiting, and is related to cumulative dose, young age, mediastinal radiotherapy and pre-existing cardiac impairment (Von Hoff et al, 1977, 1979Steinherz et al, 1991;Pein et al, 2004). It may appear early or late, and major concerns have been raised by long-term follow-up studies of children treated early in their life (Poutanen et al, 2003;Pein et al, 2004).…”

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A phase I study of intravenous liposomal daunorubicin (DaunoXome) in paediatric patients with relapsed or resistant solid tumours

et al. 2006

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Anthracyclines are widely used in paediatric oncology, but their use is limited by the risk of cumulative cardiac toxicity. Encapsulating anthracyclines in liposomes may reduce cardiac toxicity and possibly increase drug availability to tumours. A phase I study in paediatric patients was designed to establish the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) after a single course of liposomal daunorubicin, ‘DaunoXome', as a 1 h infusion on day 1 of a 21 day cycle. Patients were stratified into two groups according to prior treatment: Group A (conventional) and group B (heavily pretreated patients). Dose limiting toxicity was expected to be haematological, and a two-step escalation was planned, with and without G-CSF support. Pharmacokinetic studies were carried out in parallel. In all, 48 patients aged from 1 to 18 years were treated. Dose limiting toxicity was neutropenia for both groups. Maximum tolerated dose was defined as 155 mg m −2 for Group A and 100 mg m −2 for Group B. The second phase with G-CSF was interrupted because of evidence of cumulative cardiac toxicity. Cardiac toxicity was reported in a total of 15 patients in this study. DaunoXome shares the early cardiotoxicity of conventional anthracyclines in paediatric oncology. This study has successfully defined a haematological MTD for DaunoXome, but the significance of this is limited given the concerns of delayed cardiac toxicity. The importance of longer-term follow-up in patients enrolled into phase I studies has been underestimated previously, and may lead to an under-recognition of important adverse events.

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Cardiac Toxicity 4 to 20 Years After Completing Anthracycline Therapy

Abstract: --The 23% incidence of late cardiac abnormalities warrants continued evaluation of patients after anthracyclines to guide patient care and the design of future chemotherapeutic protocols.

Cited by 820 publications

References 12 publications

Cardiac abnormalities 15 years and more after adriamycin therapy in 229 childhood survivors of a solid tumour at the Institut Gustave Roussy

Cardiac abnormalities 15 years and more after adriamycin therapy in 229 childhood survivors of a solid tumour at the Institut Gustave Roussy

The effect of monohydroxyethylrutoside on doxorubicin-induced cardiotoxicity in patients treated for metastatic cancer in a phase II study

A phase I study of intravenous liposomal daunorubicin (DaunoXome) in paediatric patients with relapsed or resistant solid tumours

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