Avoiding heart failure after cancer drugs - new hope for early diagnosis, treatment and prevention of cardiotoxicity

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Epirubicin is an anthracycline. Anthracyclines are effective in a wide range of cancers. However, cardiotoxicity, particularly at high doses, is a major side effect limiting their use. An estimated 10 to 15 % of patients develop congestive heart failure after anthracycline treatment. Post-treatment heart damage provides a growing challenge for doctors as survival rates increase with the use of these highly effective cancer drugs. For example, studies have shown that in children treated for leukaemia 65% of survivors have progressive cardiac abnormalities six years after completing anthracycline treatment.

The Italian team led by Dr Daniela Cardinale, measured troponin I (TnI) plasma concentration in 211 poor prognosis breast cancer patients during and shortly after high dose chemotherapy. About half the patients had been treated with anthracyclines and the remainder had received prior treatment with anthracyclines before receiving other types of chemotherapy. The researchers assessed left ventricular ejection fraction (LVEF)***, an index of ventricular function, 1 to 12 months after the end of treatment. All patients had normal TnI levels before each treatment. But, a third of patients had raised TnI levels after treatment and the researchers found a close correlation between elevated levels of TnI and a decrease in left ventricular function.

Dr Cardinale said that many recent studies had explained the value of TnI in the diagnosis and risk assessment of acute coronary syndrome. But her team's study investigated whether TnI measurement gave significant information also in a population of patients with aggressive breast cancer undergoing high dose chemotherapy.

Their data demonstrated that TnI was a risk marker for future development of significant LVEF reduction. This information could not be obtained by conventional criteria such as electrocardiograpic and echocardiographic changes, or from symptoms, she said.

"The innovative aspect of this new marker is that it gives us information long before functional impairment can be detected with other techniques. The possibility of identifying patients who will develop late myocardial function depression is a golden opportunity for both oncologists and cardiologists. It can permit oncologists to modify or discontinue a regimen or shift patients towards a less cardiotoxic schedule. It could also allow cardiologists to support cardiac function or to prevent heart dysfunction with cardioprotective agents or cardiovascular therapy."

The Danish team, lead by Dr Benny Jensen, examined left ventricular function in breast cancer patients treated with epirubicin. They found that cardiotoxicity was closely correlated with the cumulative dose. However, there was a striking variation among the patients and a dramatic increase in susceptibility in older patients. They detected a progressive decrease in cardiac function beginning three months or more after the start of chemotherapy. Three years after treatment nearly 60% had experienced a 25% decrease in left ventricular function and within five years a fifth of the patients treated with high dose epirubicin had developed severe cardiomyopathy. The more severe the cardiotoxicity the longer was the time lag before it revealed itself.

They concluded that assessing left ventricular function during or immediately after chemotherapy was unlikely to predict cardiotoxicity and that monitoring was essential for months or even years after treatment. Current monitoring guidelines should be revised to take this into account, they said.

However, the time lag between chemotherapy ending and progressive cardiac deterioration occurring provided an opportunity for doctors to intervene. The researchers are currently awaiting results from a placebo-controlled study investigating whether prescribing ACE**** inhibitors once chemotherapy is completed can actually prevent cardiotoxicity.

In earlier studies the research team used ACE inhibitors to treat patients who developed decreased cardiac function after anthracyclines. Dr Jensen said: "The patients did not spontaneously recover during the observation period. Function could only be reversed by ACE inhibition for several months. We have now successfully treated more than 60 patients with severe congestive heart failure and achieved a remarkably long-lasting recovery."
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* Myocardial injury revealed by plasma troponin 1 in breast cancer treated with high-dose chemotherapy. Annals of Oncology. D Cardinale et al. Vol 13. No 5. pp 710-715.

** Functional monitoring of anthracycline cardiotoxicity: a prospective, long-term observational study of outcome in 120 patients. Annals of Oncology. B.V. Jensen et al. Vol 13. No5. pp 699-709.

*** Left ventricular ejection fraction (LEVF): The left ventricle is the chamber of the heart that squeezes to eject the blood out into the arteries. A certain amount of blood is always left behind in the ventricle awaiting the next squeeze. The percentage of blood that is pumped into the arteries with each squeeze is the left ventricular ejection fraction. An LVEF that is too low is a warning sign of possible heart dysfunction or weakness.

**** ACE inhibitors (angiontensin-converting enzyme inhibitors). Drugs that inhibit the conversion of a peptide called angiotensin I into angiotensin II. Angiotensin II constricts blood vessels and stimulates the release of two hormones, vasopressin and aldosterone, which raise blood pressure. ACE inhibitors have a valuable role in treating heart failure when other blood pressure lowering drugs such as beta-blockers cannot be used or fail to work.

MW Communications