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Key Words
chemotherapy, congestive heart failure, doxorubicin (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary ³.)

Summary
A new study suggests that the drug doxorubicin (Adriamycin®), widely used in cancer chemotherapy, causes congestive heart failure more frequently and at lower doses than has been reported in the past.

Source
Cancer, June 1, 2003; published online May 19, 2003 (see the journal abstract of the study).

Background
Doxorubicin is a highly effective anti-cancer drug but treatment with it increases patients’ risk of congestive heart failure (CHF). In CHF, the heart has trouble beating normally because of damage to the heart muscle.

A study published in 1979 showed that the risk of doxorubicin-related CHF rose as the total dose of the drug increased. The investigators estimated that 7 percent of patients developed CHF after receiving a total dose of doxorubicin of 550 milligrams per square meter (mg/m2). Because of limitations in the design of this study, the authors cautioned that they could have underestimated the full extent of the risk.

In the 1990s, Sandra Swain, M.D., and her colleagues showed in three clinical trials that a drug called dexrazoxane (Zinecard®) offered protection against doxorubicin’s adverse effects on the heart. In those trials, patients with breast cancer or small-cell lung cancer were treated with multiple-drug regimens that contained doxorubicin. They were randomly assigned to receive, in addition, either dexrazoxane or a placebo (an inactive pill).

Swain conducted these studies while she was a researcher at Georgetown University and, later, a physician with Salick Health Care, Inc., a provider of outpatient oncology services. She is now chief of the National Cancer Institute’s Cancer Therapeutics Branch.

The Study
To more accurately evaluate the risk of CHF from treatment with doxorubicin, Swain and her colleagues looked back at the medical records of 630 patients who received a placebo instead of dexrazoxane in the three trials conducted in the 1990s. Patients were followed up to find out whether they had experienced CHF at any time, either while they were enrolled in the study or later.

Results
A total of 32 of the 630 patients (5 percent) had doxorubicin-related CHF. In 11 cases, the CHF occurred while the patient was enrolled in the trial; in the other cases, it occurred later. Ten of 172 patients (6 percent) aged over 65 experienced the problem, compared with 22 of 458 patients (5 percent) aged under 65.

Like the researchers who conducted the 1979 study, Swain and her colleagues estimated that the percentage of patients with doxorubicin-related CHF rose with increasing doses of the drug. At a dose of 550 mg/m2, they estimated that 26 percent of patients would experience this adverse event. The estimate rose to 48 percent at a dose of 700 mg/m2.

A total of 149 patients (24 percent) experienced a “cardiac event” (either CHF or a test result indicating that the heart is pumping less blood than normal) while enrolled in the study. Swain and her colleagues estimated that, at a dose of 550 mg/m2, 65 percent of patients would have a cardiac event.

“Our study shows that doxorubicin can result in CHF more frequently and at lower doses than previously reported,” says Swain. Patients aged over 65 may be at higher risk and may benefit from receiving doxorubicin by infusion instead of intravenously. Infusion carries a lower risk for heart problems.

Swain recommends that all patients with metastatic breast cancer who receive more than 300 mg/m2 of doxorubicin also receive dexrazoxane to minimize the risk of heart problems. (Dexrazoxane is only approved for breast cancer patients with disease that has spread, and only after they’ve received a cumulative dose of doxorubicin of 300 mg/m2.)

Limitations
The study was supported by Pharmacia, Inc., the drug company that makes both doxorubicin and dexrazoxane.

Some patients assigned to the placebo group were switched to dexrazoxane when it became clear that this drug offered protection against heart problems. These patients were not followed up after the study. Also, patients were followed after the study for differing periods of time. These limitations may have affected the accuracy of the researchers’ estimates of the risk of doxorubicin-related CHF.

Glossary Terms

Treatment with drugs that kill cancer cells.

Weakness of the heart muscle that leads to a buildup of fluid in body tissues.

The active ingredient in a drug used to treat severe side effects caused by certain anticancer drugs. Under the brand name Totect it is used to treat the toxic effects of an anticancer drug that leaks from a vein into surrounding tissue and causes tissue damage. Under the brand name Zinecard it is used to reduce heart damage in women given doxorubicin for breast cancer that has spread. Dexrazoxane is also being studied in the treatment of cancer. It is a type of cardioprotective agent, a type of chemoprotective agent, and a type of topoisomerase inhibitor.

A drug that is used to treat many types of cancer and is being studied in the treatment of other types of cancer. Doxorubicin comes from the bacterium Streptomyces peucetius. It damages DNA and may kill cancer cells. It is a type of anthracycline antitumor antibiotic. Also called Adriamycin PFS, Adriamycin RDF, doxorubicin hydrochloride, hydroxydaunorubicin, and Rubex.

A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion.

Injection into a vein.

A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial.

A treatment plan that specifies the dosage, the schedule, and the duration of treatment.