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Chemotherapy Agents Differ in Long-Term Cardiac Risks

Pediatric patients receiving chemotherapy.

Although anthracyclines—chemotherapeutic agents that are extracted from Streptomyces bacterium—can be highly effective in the fight against various pediatric cancers, they carry a long-term risk of cardiovascular disease that continues to impact patients well into their adult lives. While this much is well known, the impact of specific anthracyclines on cardiac risk has not been adequately studied. In a study published in JAMA Oncology, researchers have now identified the relative long-term cardiac risks of a number of different chemotherapeutic agents.

"Exposure to anthracycline chemotherapies, such as doxorubicin, has long been associated with an increased risk of cardiovascular disease in long-term childhood cancer survivors," commented Gregory Aune, MD, PhD, Assistant Professor of Pediatrics at the University of Texas San Antonio and one of the study's authors. "Previously, it was assumed that exposure to any member of the anthracycline class carried the same risk of late cardiovascular complications. By studying the outcomes of over 28,000 long-term survivors in the U.S. and Europe, this research indicates that exposure to different anthracyclines results in variable long-term cardiovascular risk."

The researchers, from the University of Texas Health Science Center at San Antonio, studied 28,423 survivors of childhood cancer treated between 1962 and 2005, using participant data pooled from a number of studies. Patients were followed for a median of 20 years (with a range of 5 to 40 years) after receiving a cancer diagnosis. Of the cancer survivors in the data pool, 399 experienced cardiomyopathy.

Using patient medical records, the researchers abstracted information on the cumulative doses of each chemotherapeutic agent and of any chest radiotherapy exposure administered to each patient. During their cancer treatment regimen, 9,330 of the patients received doxorubicin, 4,433 received daunorubicin, 342 received epirubicin, 241 received idarubicin, and 265 received mitoxantrone, which is an anthraquinone rather than an anthracycline.

The investigators found that the cardiac risks of the various chemotherapies did not always align with that which was suggested by current guidelines, which the study authors note are frequently based on the assumption that an anthracycline agent's hematologic toxicity is equivalent to its cardiotoxicity. Compared with the anthracycline doxorubicin, the anthraquinone mitoxantrone has much greater cardiotoxic risk than is suggested by current guidelines. In contrast, the anthracycline daunorubicin is associated with less cardiotoxic risk than the guidelines suggest.

The equivalence ratios for cardiotoxic risk relative to doxorubicin (with a lower number indicating lower relative risk) were 0.6 for daunorubicin, 0.8 for epirubicin, and 10.5 for mitoxantrone. For idarubicin, outcomes were too rare to generate estimates. The anthracycline epirubicin appeared to be equivalent to doxorubicin in its effects on cardiac risk.

Dr. Aune commented on the need to apply the study's results to clinical practice: "In the future, it will be important to take these differences into account when screening long-term survivors for cardiovascular complications and in the development of modern treatment regimens."

For More Information

Feijen EAM, Leisenring WM, Stratton KL, et al (2019). Derivation of anthracycline and anthraquinone equivalence ratios to doxorubicin for late-onset cardiotoxicity. JAMA Oncol. [Epub ahead of print] DOI:10.1001/jamaoncol.2018.6634

​Image credit​: Bill Branson, National Cancer Institute

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