What is doxorubicin?:
Doxorubicin (trade name Adriamycin) is a commonly used chemotherapy agent that is very effective in both Hodgkin and Non-Hodgkin lymphomas. It is used in virtually all the first-line chemotherapy regimens for lymphomas. It belongs to the class of chemotherapy drugs called anthracyclines.
Doxorubicin may cause heart damage:
It is well recognized that doxorubicin may cause damage to the heart in some individuals. While other anthracyclines (like epirubucun and mitoxantrone) may also cause heart damage, the chances are more common with doxorubicin. Doxorubicin causes both early and late heart damage (also called 'cardiotoxicity'). The early damage occurs immediately after drug administration or within 1 to 2 days. There are minor effects that are picked up on the electrocardiogram (EKG) and in most cases resolve without casing any major problems. It is the late-starting damage that is important and more serious.
Late cardiac damage with doxorubicin:
Late damage to the heart starts about a year or more after chemotherapy. Doxorubicin mainly affects the heart muscles. It weakens the heart muscles and makes the pumping of blood more difficult for the heart. When severe, it leads to a condition called congestive heart failure (CHF). Individuals with CHF complain of a number of symptoms
- a gradually worsening difficulty in strenuous work, leading to tiredness or breathing trouble when climbing stairs or walking
- a cough that worsens at night
- swelling of the feet
- difficulty in breathing at rest
If severe, CHF can cause severe disability and even death.
How does doxorubicin damage the heart?:
Doxorubicin reacts with some chemicals in the body (called enzymes) to produce harmful substances called free radicals. The production of these harmful free radicals is enhanced in organs like the heart where there is more oxygen and iron. While some organs have special enzymes to destroy these free radicals, the heart has a relatively poor supply of these enzymes. This makes the heart muscles susceptible to damage with free radicals.
Factors that affect heart damage:
Numerous factors increase the chances of heart damage with doxorubicin
- A high dose of doxorubicin is most important. The total dose of doxorubicin received during a person’s life should be ideally less than 400mg per square meter (of the body surface). The risk of CHF with this dose is less than 1 percent. At higher doses, the chances of heart damage increase. Fortunately, most chemo schedules require lower doses.
- The simultaneous use of other chemotherapy drugs that affect the heart e.g. high doses of cyclophosphamide
- Radiation treatment to the chest
- Already-existing heart disease
- Younger age
- Female patients
Testing for heart damage:
Heart damage is usually tested with an echocardiogram (commonly called an 'echo') or a MUGA scan to test for the amount of blood that the heart can pump out. In medical terms, this is called the ‘left ventricular ejection fraction’ or LVEF. The LVEF is measured for most individuals before starting treatment to rule out any pre-existing heart problem. Subsequently, it may be measured again during treatment and later periodically to see if there is a fall in the LVEF. Occasionally cardiac problems can show in the EKG as well.
Ways to reduce heart damage with doxorubicin:
There are some ways in which heart damage can be prevented or lessened
- Keeping the total dose of doxorubicin within safe limits
- Administering the drug as an infusion in saline rather than as an injection
- Using a new preparation of doxorubicin called ‘liposomal doxorubicin’ - the drug comes enclosed in a fatty coating called a liposome. This coating breaks only within the cancer to release the drug. Normal organs like the heart are less affected.
- Using a substance called dexrazoxane as an infusion soon after doxorubicin. It may reduce the chances of heart damage and is FDA approved in metastatic breast cancer.
Treatment of CCF :
Cardiac failure caused by doxorubicin is treated on the same lines as other types of heart failure. There are no special medicines for doxorubicin related heart damage. Rest, oxygen and pills reduce the symptoms of CCF and stabilize the cardiac disability. Severe symptoms may require hospital admission.
Should we stop using doxorubicin?:
Doxorubicin is an extremely effective chemotherapy drug. It has a role in the treatment of many cancers. While there is a definite association of doxorubicin with heart damage, the benefits of using doxorubicin outweigh the risks. Heart damage with this drug is quite well understood, and if doxorubicin is used within the safe dose limits, there is no reason to stop using a drug as useful as this.
Cancer - Principles and Practice of Oncology (7th Edition). Editors - Vicent T Devita Jr., Samuel Hellman, Steven Rosenberg. (Chapter 15: Pharmacology of Cancer Chemotherapy: Section 7: Topoisomerase Interactive Agents.)