Cardiac Toxicity

Overview

Chemotherapy drugs are toxins and can cause damage to your heart, which may develop into cardiac complications. As a result of this damage, the heart is unable to pump enough blood to supply the body with essential oxygen and nutrients. Although several chemotherapy drugs may cause cardiac toxicity, the most common cause of cardiac toxicity in cancer patients is treatment with chemotherapy drugs called anthracyclines.  Doxorubicin (Adriamycin®) is a frequently prescribed anthracycline.  Although the best way to currently prevent cardiac complications from anthracyclines is to limit the amount of anthracyclines administered, forms of less toxic anthracycline drugs and drugs that may relieve side effects are being developed.

What is cardiac toxicity?

Cardiac toxicity is damage to the muscles of the heart caused by chemotherapy drugs used to treat cancer. Most of the cardiac complications associated with chemotherapy occur during or shortly after the completion of therapy.  However, some of these problems can persist and become chronic. In addition, some chemotherapy drugs can cause heart damage that is only apparent months to years after the completion of cancer treatment. Heart problems can be mild and only detectable by sophisticated tests, such as determining the left ventricular ejection fraction (LVEF), or they can be severe, resulting in congestive heart failure (CHF).  Damage to the heart from cancer chemotherapy can be so severe that the patient may require a heart transplant. 

What causes cardiac toxicity?

There are specific classes of drugs, such as the anthracyclines (doxorubicin, daunomycin, epirubicin, mitoxantrone and idarubicin), that are known to cause damage to the muscle cells of the heart.  The anthracyclines are also given with other drugs, such as alkylating agents and vinca alkaloids, which can contribute to heart damage. In addition, radiation therapy to the chest wall or area around the heart can affect the blood vessels supplying the heart, leading to a myocardial infarction or “heart attack”.  Since many patients, especially with lymphoma or breast cancer, receive both anthracycline-based chemotherapy and radiation therapy, there may be a cumulative effect on the heart. The following is a brief outline of the major drugs that have been associated with long term complications to the heart:

Anthracyclines (doxorubicin, daunomycin, epirubicin, mitoxantrone and idarubicin): The anthracyclines are associated with cumulative dose-related irreversible cardiac toxicity.  In other words, the more anthracycline administered, the more likely there may be damage to the heart.  The main feature of cardiac toxicity from anthracyclines is a decreased left ventricular ejection fraction leading to congestive heart failure.  Doxorubicin is probably the most commonly administered anthracycline, and there are many studies defining the cardiac complications associated with high cumulative doses.  Although there is a rapid increase in late cardiac toxicity when patients receive cumulative doses greater than 550 mg/m2, there is some variability of individual tolerance of doxorubicin.[1] 

Researchers from Denmark have reported that cardiac toxicity of epirubicin is closely correlated with the cumulative dose, but with a great variability in individual susceptibility and a dramatic increase with advancing age.[2] They reported that the onset of cardiac toxicity following epirubicin occurred 3 months or more after administration was completed and was characterized by slowly progressive deterioration of heart function, continuing years after treatment. They estimated that 59% of the patients would experience at least a 25% reduction in heart function 3 years after 850-1000 mg/m2 of epirubicin and 20% had deterioration into congestive heart failure.

Doxorubicin has also been an integral component of most treatment regimens for Hodgkin’s disease and non-Hodgkin’s lymphoma.  However, many patients with lymphoma receive radiation to the chest, which is known to cause heart damage. Thus, when patients develop cardiac complications it has been difficult to sort out the relative contributions of chemotherapy and radiation therapy.  Physicians at St. Jude Cancer Center have evaluated the long-term effects of treating 387 pediatric patients with Hodgkin’s disease.[3] The overall survival of this group of patients was 82%.  Four percent of the deaths were due to cardiac toxicity. U.S. researchers have evaluated the effects of doxorubicin-based adjuvant chemotherapy in over 1,400 patients with localized breast cancer.[4] Ten-years from treatment with doxorubicin, the death rate from heart attack was 2.4% in the radiated patients and 0.5% in the patients who did not receive radiation therapy. Although the rates of heart attack were increased, the authors of this study did not think this was an excessive rate in either the radiation or non-radiation therapy group.

What are the symptoms of cardiac toxicity?

The symptoms of cardiac toxicity are related to the inability of the heart to pump blood efficiently to vital areas of the body.  The earliest sign of heart failure is typically fatigue, which can be worsened by anemia. Patients then develop shortness of breath with activity, which can worsen to shortness of breath at rest.  Progressive congestive heart failure is associated with weight gain and swelling of the ankles. 

How is cardiac toxicity prevented?

Heart problems may be prevented by altering the amount of drug administered (dose), the method of administration and the type of anthracycline administered. Also, medication that can prevent damage from doxorubicin may be administered.

Dose: The main way to prevent cardiac toxicity is to limit the cumulative dose of drugs that damage the heart, especially the anthracyclines. There is a defined amount of doxorubicin that can be given with a lesser risk of complications:

  • If your total dose of doxorubicin is less than 550mg/m2, there is a less than 1% chance that you will experience cardiac toxicity.
  • If your total dose of doxorubicin is between 560-1155mg/m2, your risk increases to 30%.

Also, there appears to be individual differences in how much patients can tolerate doxorubicin.[5] For example, some patients may receive high doses of doxorubicin without ever developing heart damage, while some have problems at relatively low doses (i.e. less than 550mg/m2 total dose).

Method of administration: There is also some evidence that the method of drug administration may affect the risk of cardiac toxicity.  Rapid administration of drugs results in high blood levels, which may cause more heart damage than the same amount of drug given over a longer period of time. Giving smaller doses more frequently can also decrease the toxicity compared to large doses of drugs at longer intervals.

Liposomal anthracyclines: The risk of cardiac toxicity from anthracyclines has been reduced by making them in a different way. Liposomal anthracyclines have been encapsulated, or encased, in a liposome, a tiny globule of fat. By “hiding” the drug in fat, it stays in the body longer because the immune system doesn’t target it for elimination and the liver doesn’t break it down as quickly. Studies to date indicate that the risk of heart problems is considerably lower with liposomal doxorubicin formulations than with conventional doxorubicin.[6]

Types of liposomal anthracyclines include:

  • Liposomal daunorubicin (DaunoXome®)
  • Pegylated liposomal doxorubicin (Doxil®)

Pegylated liposomal doxorubicin has been studied most extensively and has demonstrated the most significant reductions in heart problems. Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin, but with less cardiac toxicity.

Dexrazoxane (Zinecard®): This drug has been shown to prevent or reduce the severity of heart damage caused by doxorubicin.[7] Dexrazoxane is thought to protect the heart muscle by blocking the formation of oxygen free radicals. One of the ways that radiation and chemotherapy drugs damage cells is by forming free radicals. Free radicals are unstable molecules which are formed during many normal cellular processes that involve oxygen, such as burning fuel for energy. They are also formed from exposure to elements in the environment, like tobacco smoke, radiation and chemotherapy drugs.

How is cardiac toxicity treated?

Patients with anthracycline induced heart failure are generally treated the same as patients with heart failure from other causes. This usually means diuretics to control fluid accumulation and digitalis drugs to strengthen the heart. If progressive and severe, the only treatment may be a heart transplant.

References

[1]Iarussi D, Indolfi P, Casale F, et al. Recent Advances in the Prevention of Anthracycline Cardiotoxicity in Childhood. Cur Med Chem. 2001;13:1649-1660.

[2]Jensen BV, Skovsgaard T, Nielsen SL, et al. Functional Monitoring of Anthracycline Cardiotoxicity: A Prospective, Blinded, Long-Term Observational Study of Outcome in 120 Patients. Ann Oncol. 2002;13:699-709.

[3] Hudson MM,Poquette CA, Lee J, Increased mortality after successful treatment for Hodgkin’s disease. J Clin Oncol. 1998;16:3592-600.

[4]Woodward WA, Strom EA, McNeese MD, et al. Cardiovascular death and second non-breast cancer malignancy after postmastectomy radiation and doxorubicin-based chemotherapy. Int J Radiat Oncol Biol Phys. 2003;57:327-35.

[5]Iarussi D, Indolfi P, Casale F, et al. Recent Advances in the Prevention of Antharcycline Cardiotoxicity in Childhood. Cur Med Chem. 2001;13:1649-1660.

[6] Safra T.Cardiac safety of liposomal anthracyclines. Oncologist. 2003;8 Suppl 2:17-24.

[7] Speyer JL et al.: Protective effect of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer. N Engl J Med 1988;319:745-752.

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