Epirubicin

Epirubicin is a chemotherapeutic drug that is used for the treatment of breast cancer that has spread to the lymph nodes following breast cancer therapy. It can have serious side effects of heart failure and leukemia, which can occur months or years after stopping treatment.

Epirubicin's brand name is Ellence. Other brand names include Pharmarubicin and Epirubicin. Epirubicin was available in the United Kingdom before it was approved by the Food and Drug Administration (FDA) in 1999. It is marketed by Pfizer. Epirubicin has other non-FDA approved uses to treat other forms of cancers.

Development of Epirubicin

Epirubicin belongs to the class of chemotherapeutic drugs called anthracyclines. It, like all anthracyclines, is derived from the bacteria Streptomyces peucetius. Epirubicin is made by slightly altering the structure of the naturally-occurring anthracycline.

Uses/Indications

Epirubicin is used to treat breast cancer that has spread (metastasized) to the lymph nodes under the arms, the axillary lymph nodes. It is used as adjuvant (additional) treatment, which is given after primary treatment such as surgery. Only women who naturally overproduce a protein called HER2-neu in breast cells, HER2-neu-positive, respond well to treatment with epirubicin.^[1] Clinical trials are now underway to investigate epirubicin as a treatment for gastric cancer.

Removal of breast and a sample of underarm lymph nodes.

How Epirubicin Is Taken

Epirubicin is available as single-dose injections of 50 mg/25 ml or 200 mg/100 ml. Typically, epirubicin is given intravenously over 15-20 minutes at a starting dose of 100-120 mg/m² (square meter of body surface area). Lower doses, such as 75-90 mg/m², may be used in patients who may not tolerate the regular dose. Epirubicin is given in repeated three- or four-week cycles. The dose can be given either on day one of the cycle or split into two doses given on day one and day eight of the cycle. Dosage can be adjusted based on the response. Other drugs such as cyclophosphamide and fluorouracil are combined with epirubicin in the chemotherapeutic cycle. Most often antibiotics are infused with epirubicin.

How Epirubicin Works

Epirubicin prevents cells from replicating (cytostatic) and kills them (cytotoxic). It forms complexes between the base pairs of DNA in both healthy and cancerous cells. Interaction with healthy cells is responsible for all the side effects associated with the use of epirubicin. The disruption of DNA prevents the cell from replicating and producing proteins. Epirubicin also prevents the cell from fixing its DNA and also produces free radicals that damage the cells even further.

Cancer cells can develop resistance to epirubicin. Cells adapt to epirubicin by pumping the drug out of the cells, changing the structure or activity of proteins that interact with epirubicin, or by enhancing DNA repair.

How the Body Affects Epirubicin

Epirubicin is primarily metabolized (broken down) by the liver into several different compounds. It is excreted in both feces and urine.

In special populations

In females, the removal of epirubicin from the body (clearance) is dependent on age. clearance of epirubicin is over 30% slower in females aged 70 years of age compared to those 25 years old.^[2] In addition to age, kidney or liver damage can reduce the elimination of epirubicin from the body.

The elimination of epirubicin has not been determined in children or in races other than Caucasian.

Side Effects

Epirubicin causes several side effects, some of which can be severe. In some cases, epirubicin may need to be stopped because of these side effects.

One of the most dangerous side effects of epirubicin is heart damage. In its most severe form, this heart damage manifests as congestive heart failure, which can be fatal. Heart problems can occur months or years after stopping epirubicin. The probability of developing heart failure is dependent on the cumulative dose of epirubicin, which is the total amount of epirubicin given after all chemotherapy cycles are finished.^[2] The risk of congestive heart failure has been estimated to be 0.9% following a cumulative dose of 550 mg/m² and 3.3% after a cumulative dose of 900 mg/m² At even higher doses the risk of congestive heart failure increases drastically.

Leukemias have also been reported within three years of stopping epirubicin. Based on several studies, the risk of leukemia has been estimated at 2% after eight years.^[3]

The following are some common side effects associated with the use of epirubicin:

• Reddish urine(for 1-2 days)
• Nausea
• Vomiting
• Mouth sores
• Dehydration
• Diarrhea
• Signs of congestive heart failure (e.g., shortness of breath, ankle swelling)
• Fever
• Signs of infection
• Pain, burning or stinging at the injection site
• Reversible alopecia (hair loss)
• Low blood cell counts (anemia, leukopenia, neutropenia, and thrombocytopenia)
• Fatigue
• Temporary or permanent loss of menstrual cycle in women
• Hot flashes
• Rash/itch

Epirubicin may cause an inflammation reaction (swelling, tenderness, or redness) at the site of treatment with radiation.

Risks and Precautions

Because of its side effect profile, epirubicin should not be used in patients who have the following:

• Low levels of white blood cells
• Severe liver problems
• Previous treatment with anthracyclines up to the maximum total dose
• Severe heart failure or a recent heart attack
• Allergic reactions to epirubicin or related drugs

Several medications that are harmful to the heart can increase the risk of developing heart problems:

• Other anthracyclines or drugs called anthracenediones
• Herceptin)
• Calcium channel blocker such as nifedipine (Adalat or Nifedical)

Leukemia is more likely to develop with the following:

• If epirubicin is given with other anticancer drugs that damage DNA

• When the dose of epirubicin has been escalated

• If pretreatment involved high doses of other drugs that kill cells.

Side effects can be more severe or frequent if epirubicin is given with other chemotherapeutic drugs and cimetidine (Tagamet).

Epirubicin causes birth defects. Women should avoid becoming pregnant or nursing an infant while receiving treatment. A physician should be notified if the patient is pregnant or becomes pregnant while receiving epirubicin. Men, as well as women, should use contraceptives while on epirubicin because it can damage sperm.

Drug Interactions

The levels of epirubicin in the blood are increased when it is given with the anticancer drug paclitaxel (Taxol) or the ulcer drug cimetidine (Tagamet). Whether the higher concentrations of epirubicin increase the risk of developing side effects is not known. Trastuzumab (Herceptin), another treatment for breast cancer, given with epirubicin can increase the risk of developing heart problems.

Clinical Trials

Epirubicin used in combination with other chemotherapeutic agents slightly improves survival over treatments that do not use epirubicin. The National Epirubicin Adjuvant Trial and the BR9601 trial examined the effectiveness of epirubicin in the adjuvant treatment of early breast cancer.^[4] Analysis of the trials found that outcomes were improved in patients treated with four cycles of epirubicin followed by four cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF) compared to treatment with CMF alone. The 5-year survival of women without relapse was 76% with epirubicin and 69% with only CMF. Five-year Survival with or without cancer relapse was 82% for women receiving Ellence and 75% for those who received CMF alone. Side effects did occur more frequently in women receiving epirubicin.

A study by the National Cancer Institute of Canada showed that epirubicin was superior to treatment with CMF in premenopausal women with breast cancer.^[5] Survival without relapse of cancer after five years was 63% in women treated with cyclophosphamide, epirubicin, and fluorouracil compared to 53% for women receiving CMF. Almost 8% of the women treated with Ellence survived with or without relapse over five years, whereas 70% of the women receiving CMF survived after five years.

External Links

• Drugs.com: Epirubicin Drug Interactions
• Pfizer: Ellence
• RXList Ellence Epirubicin Hydrochloride: Drug Warnings and Precautions
• Drugs.com: Complete Epirubicin Hydrochloride Information
• breastcancer.org Main Page

References

1. ↑ Gennari A, Sormani MP, Pronzato P, et al. HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 2008;100(1):14-20. PMID 18159072
2. ↑ ^{2.0 2.1} Pfizer. Epirubicin Product Information. [http://www.pfizer.com/files/products/uspi_ellence.pdf PDF].
3. ↑ Crump M, Tu DS, Shepherd L, Levine M, Bramwell V, Pritchard K. Risk of acute leukemia following epirubicin-based adjuvant chemotherapy: a report from the National Cancer Institute of Canada Clinical Trials Group.] J Clin Oncol 2003;21:3066-71. PMID 12915595
4. ↑ Poole CJ, Earl HM, Hiller L, et al. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med 2006;355:1851-62. PMID 17079759
5. ↑ French Adjuvant Study Group. Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study Group 05 randomized trial. J Clin Oncol 2001;19:602-11. PMID 11157009