Study Indicates Heart Damage From Some Cancer Drugs Worsens Over The Years

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 today (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

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

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

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.

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.

Annals of Oncology is the monthly journal of the European Society for
Medical Oncology.
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