Preventing Anthracycline Cardiotoxicity in Pediatric Survivors

November 1, 2002

NIAGARA-ON-THE-LAKE, On-tario, Canada-The cardiotoxicity of anthracyclines can occur many years after treatment for childhood cancer. Studies exploring methods to prevent these effects were presented at the 7th International Conference for Long-Term Complications of Treatment of Children and Adolescents for Cancer, hosted by Ros-well Park Cancer Institute.

NIAGARA-ON-THE-LAKE, On-tario, Canada—The cardiotoxicity of anthracyclines can occur many years after treatment for childhood cancer. Studies exploring methods to prevent these effects were presented at the 7th International Conference for Long-Term Complications of Treatment of Children and Adolescents for Cancer, hosted by Ros-well Park Cancer Institute.

A group of researchers from the Gustave-Roussy Institute, Villejuif, France, confirmed heart damage in a group of childhood cancer survivors who received anthracycline therapy (abstract 9). Late cardiotoxicity (15 years post-diagnosis) was found to be a health concern for 88 of 230 patients (38%), Dr. F. de Vathaire said.

Using a Cox model, the researchers confirmed that cumulative dose of anthracycline and the average radiation dose to the heart—but not sex or age at treatment—were risk factors for cardiac impairment. The health risks increased with increased drug dosages.

To counter these type of effects, researchers from the Great Ormond Street Hospital for Children, London, UK, investigated a method of lengthening anthracycline infusion time to possibly decrease cardiotoxicity (abstract 11).

The team, led by Dr. Gill Levitt, found no differences in cardiotoxicity between acute lymphoblastic leukemia (ALL) patients treated in a standard manner (bolus dosing) and patients who received the drugs via a 6-hour dosing schedule. Cardiac abnormalities appeared in 24% of both groups.

The patients received their cumulative 180 mg/m2 daunorubicin dose while participating in two different studies in England: UKALL X (bolus dose) and UKALL XI (6-hour infusion). The cohort consisted of 40 ALL survivors from UKALL X and 71 ALL survivors from UKALL XI. Cardiac performance in the cancer patients was compared with that in 100 normal children.

US Enalapril Study

A study from the United States, the ACE-Inhibitor after Anthracycline (AAA) study, compared enalapril (Vasotec) with placebo as a means of preventing cardiac deterioration in pediatric cancer survivors (abstract 12).

"We have known for years about the damage caused by anthracyclines to the heart. However, we also know that these drugs are very effective in curing children of cancer. We need to learn how to minimize the damage and still retain the effectiveness," said Jeffrey H. Silber, MD, PhD, attending physician, Children’s Hospital of Philadelphia. "We think that the use of enalapril may stave off some of the complications caused by heart damage and help affected survivors maintain a higher quality of life."

It is known that anthracyclines damage the heart by thinning the walls. A decrease in wall thickness can lead to increased left ventricular end systolic wall stress, and increased stress can lead to heart problems such as congestive heart failure. Initial damage from anthracy-clines can lead to a vicious cycle (see Figure) that sometimes may take 20 years or longer to manifest itself. Enalapril blocks an increase in renin, which may inhibit the cycle and minimize the negative effects on the heart.

The AAA study enrolled 135 patients who screened positive for anthracycline cardiotoxicity; they were randomized to receive either enalapril or placebo for a median of 3 years (range, 2 to 7).

There was no difference in the rate of change of the maximal cardiac index at peak exercise between the groups. However, during the first year of treatment, the change in left ventricular end systolic wall stress (LVESWS) was greater in the enalapril group than the placebo group (-8.59 g/cm2 vs -1.85 g/cm2, P = .033), and this difference was maintained over time with a 9% reduction in LVESWS at 5 years in the enalapril group, compared with placebo.

"After the study ended, we learned that six of seven patients who were removed from the study due to significant heart deterioration were initially in the placebo group," Dr. Silber said. "Enalapril can be used safely, but it cannot reverse the damage to the heart. The risks and side effects of long-term ACE-inhibitor use must be considered against these potential benefits. All the enalapril can do now is buy us some time until another drug or therapy comes along for this large group of survivors."