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Dexrazoxane for anthracycline extravasations well-tolerated
Prompt treatment of extravasations can reduce and potentially prevent serious tissue damage.
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Extravasation reactions are some of the most devastating adverse effects of anthracycline antineoplastic agents.
Extravasation with most other chemotherapy agents leads to no adverse reactions or to self-limited irritation of the tissues. However, vesicant chemotherapy agents, which include the vinca alkaloids, anthracyclines and others, can lead to tissue necrosis, severe pain and ulceration of the skin and underlying tissue. In some cases, the tissue damage requires surgery and skin grafting to heal adequately.
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Approximately 25% to 50% of anthracycline extravasations progress to ulceration and severe tissue damage. With anthracycline vesicant reactions, the lesions can appear and expand during a period of weeks due to continued tissue damage from the retained drug molecules. Prevention and adequate treatment during these situations are critical.
Prevention and treatment
Extravasation situations can result from different causes, including malfunction of central lines, small fragile peripheral veins, recent venipuncture, needle insertion technique, vessel size and others. There are certain techniques and practices that can reduce the risk for extravasation. However, even with the most expert techniques and experience, not all extravasation episodes can be prevented.
Prompt treatment of an extravasation episode can reduce and potentially prevent serious tissue damage. Pharmacologic treatments (antidotes) and non-drug therapy (hot and cold packs) are recommended for some chemotherapy agents.
In the case of anthracyclines, the standard treatment until now has been the application of cool or cold packs to reduce the diffusion of anthracycline molecules. These cooling measures should be applied right away and then alternated on and off for a day or two.
In addition, studies have shown the benefit of the topical application of dimethyl sulfoxide. This solvent is thought to act as a free-radical scavenger and antioxidant. The recommended treatment is to apply 1.5 mL to the skin over twice the area of extravasation and allow to dry. This should be repeated every six to eight hours for seven to 14 days.
Dexrazoxane
Following several case reports, dexrazoxane (Zinecard, Pfizer) has been investigated for the treatment of anthracycline extravasations. Dexrazoxane is a derivative of ethylenediaminetetraacetic acid and acts as an intracellular chelating agent, as well as an inhibitor of type II topoisomerase.
This agent is approved as a treatment to reduce the cardiotoxicity associated with doxorubicin (Adriamycin, Pharmacia) administration in patients with metastatic breast cancer. Its activity is thought to be due to interference with free-radical generation mediated by iron molecules by acting as a chelating agent. Dexrazoxane has a half-life of two to 2.5 hours and a large volume of distribution.
Although this agent is somewhat metabolized, renal excretion accounts for most of the drug elimination. The usual dose when used with doxorubicin to reduce cardiotoxicity is 500 mg/m2 IV before each 50 mg/m2 IV dose of doxorubicin. The main adverse effects include injection site pain, diarrhea, nausea, vomiting and myelosuppression.
Recent results
In the Annals of Oncology, researchers recently reported the results of two open-label, prospective trials studying the effects of IV dexrazoxane in anthracycline extravasa-tion episodes.
The two trials were similar in design and were combined in analysis. Patients who had biopsy-proven (fluorescence microscopy) anthracycline extravasations were treated with dexrazoxane. The patients received epirubicin (Cerubidine, Bedford Labs), doxorubicin and daunorubicin (Pharmorubicin, Pfizer), and the majority of extravasations were noted during the first three courses of chemotherapy. Most patients had breast cancer or lymphoma.
The dexrazoxane was administered as soon as possible after the incident and not longer than six hours. The dose was 1,000 mg/m2 IV (infused into the opposite arm from the extravasation) during the course of one to two hours and repeated at 1,000 mg/m2 IV at 24 hours and then at 500 mg/m2 IV at 48 hours.
In this trial, treatment with dimethyl sulfoxide or corticosteroids was not allowed, but topical cooling was permitted. The patients were followed daily for three days and then assessed weekly for one month and again on day 90.
This trial showed excellent results. Only one patient of the 54 assessable patients (out of 80 total) required surgical intervention to resect the necrotic area. Some patients suffered from sensory disturbances, skin atrophy, pain and limited movement, but these were generally mild and affected 2% to 17% of the patients.
Side effects
Dexrazoxane treatment was well-tolerated. The most frequently reported side effects were superficial phlebitis and injection site reactions (35%, mostly grade 1 or grade 2). Other reported adverse effects include nausea, wound infections, vomiting, fever, alopecia, anemia, neutropenia and increased liver function tests, which are all consistent with administration of chemotherapy regimens for breast cancer and lymphoma.
In conclusion, dexrazoxane appears to be a well-tolerated, effective treatment for anthracycline extravasation.
For more information:
- Lisa K. Lohr, PharmD, BCPS, BCOP, is Clinical Leader of Oncology and Bone Marrow Transplantation in the Department of Pharmacy Services at the University of Minnesota Medical Center, Fairview. She is also the Pharmacology section editor of Hem/Onc Today.
- Ener RA, Meglathery SB, Styler M. Extravasation of systemic hemato-oncologic therapies. Ann Oncol. 2004;15:858-862.
- Goolsby TV, Lombardo FA. Extravasation of chemotherapeutic agents: Prevention and Treatment. Semin Oncol. 2006;33:139-143.
- Mouridsen, HT, Langer SW, Buter J, et al. Treatment of anthracycline extravasation with Savene (dexrazoxane): results from two prospective clinical multicentre studies. Ann Oncol. 2007;18:546-550.