Study indicates heart damage from some cancer drugs worsens over the years

Life-long monitoring important for patients treated by anthracylines say Dutch researchers

It is well documented that some anti-cancer drugs can damage the heart, but a long-term follow-up of children and young adults who had doxorubicin[1] treatment for bone tumours suggests that the damage gets progressively worse as the years go on.

In a study published on-line (Thursday 20 July) in Annals of Oncology[2] researchers from the University Medical Centre at the University of Groningen in the Netherlands, say that all patients treated with drugs known as anthracyclines should have life-long cardiac monitoring.

Their study followed 22 patients, who had been treated with moderate or high doses of doxorubicin for osteogenic sarcomas or malignant fibrous histiocytomas, for a median time of 22 years (between 15 and 27.5 years). It is believed to be the longest prospective follow-up to evaluate heart function in children, adolescents and young adults treated with anthracylines.

The researchers found over a quarter had systolic dysfunction and nearly half had diastolic dysfunction and that this was a further deterioration in heart function compared to an earlier follow-up when fewer than one in ten had systolic dysfunction and less than a fifth had diastolic dysfunction.

Lead researcher Dr Inge Brouwer, from the subdivision of paediatric oncology at the centre, said: "We undertook this long-term study because since it's known that overt heart failure has been found in up to 5% of cancer survivors treated with anthracyclines it was possible that subclinical abnormalities might be even more frequent. The natural course of subclinical abnormalities was largely unknown and it was unclear whether we could expect progressive cardiac deterioration."

There were 31 long-term survivors in the original group of patients treated between 1977 and 1999. Most were children and adolescents but the age range was 10 to 38. All had cardiac assessment nine years after treatment. Twenty-nine were re-assessed 14 years after treatment, and 22 in the present round of assessment. Of the original group, one died from congestive heart failure; one from a second cancer; two who were already known to have an abnormal heart function were excluded because they had received thoracic radiotherapy for a second cancer; one had a terminal neurodegenerative disease and four refused to take part.

In addition to a physical examination and medical history the assessment involved blood tests and blood pressure measurements, Doppler echocardiography, a static ECG and 24-hour ECG monitoring during normal activities. Systolic and diastolic function tests showed how well the heart's left chamber was pumping (systolic function) and relaxing (diastolic function).

Dr Brouwer said: "We found progressive impairment of systolic and diastolic function. We also found a deterioration in heart rate variability (HRV) in the 19 of the 22 patients whose HRV we were able to evaluate. HRV is the alteration in the beat-to-beat rate of the heart and reduced HRV is a marker for potential heart problems.

"Forty-five per cent of the 22 long-term survivors, whose median age is now 39, had diastolic dysfunction compared with 18% in 1997 and 27% had systolic dysfunction compared with 9% in 1997. The six patients with impaired systolic function also had abnormalities in the motion of the heart wall with suggestions of ischaemic heart disease in two of them. In addition, we knew that three of the nine patients who did not take part in this latest assessment, have or had cardiac dysfunction."

She said that other studies involving moderate term follow-up of anthracyline-treated cancer survivors had produced conflicting results with some showing progressive abnormalities, while others showed no further deterioration. "We also found unchanged systolic function at our moderate term follow-up and now subsequently a further decrease, but our study, although small, has a 22-year median follow-up, which is considerably longer than most others, which have been about 13 years."

"Our results suggest that after treatment with anthracyclines there is an ongoing deterioration of cardiac function and it is possible that this deterioration will continue, although we don't know if and when there will be further progression. For this reason regular echocardiography seems important to monitor heart function. Most doxorubicin-treated survivors with cardiac abnormalities that show up on echocardiography have no cardiac complaints. We need to keep checking them and be ready to start medication to stabilise their heart function in order to prevent further cardiac deterioration and development of cardiac complaints. It is important to be ready to treat cardiovascular risk factors for example, high blood pressure or cholesterol and to encourage patients to make helpful lifestyle changes such as stopping smoking, reducing their weight if necessary and taking exercise."

Dr Brouwer added that cardiotoxicity from anthracycline treatment is an issue in all cancer survivors that used this treatment, not just bone tumours. Although some studies have found younger people to be more at risk of heart damage, their study has not found young age was a factor. They are to continue their follow-up and expand their ongoing study to include all childhood cancer survivors treated at the University Medical Centre in Groningen.

But, she concluded by stressing that doxorubicin was a highly effective treatment and the cure of cancer was still the first priority. Patients now also tended to receive lower doses of doxorubicin although there were still some who needed high doses. If there is was a deterioration in heart function during treatment, doses were normally reduced. Furthermore, there were cardioprotective drugs, such as dexrazoxane available now, which were not available to earlier patients.

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[1] Doxorubicin. Used to treat a wide range of cancers. It is one of a group of drugs known as anthracyclines. Anthracyclines act to prevent cell division by disrupting the structure of the DNA and terminate its function.

[2] Long-term cardiac follow-up in survivors of as malignant bone tumour. Annals of Oncology.doi:10.1093/annonc/mdl156.

A PDF of the research paper is available on request. Please acknowledge Annals of Oncology as a source in any reports.

Annals of Oncology is the monthly journal of the European Society for Medical Oncology. Annals of Oncology website: http://annonc.oxfordjournals.org/

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