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Published on 1 September 2007

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Recent advances in anthracycline extravasation treatment

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Lisa Schulmeister
RN MN APRN-BC OCN® FAAN

Oncology Nursing Consultant/Adjunct Assistant Professor of Nursing

Louisiana State University Health Sciences Center
New Orleans
USA

E: LisaSchulmeister@hotmail.com

Anthracycline chemotherapy agents (eg, ­daunorubicin, doxorubicin, epirubicin and idarubicin) have been used to treat various types of cancer since the early 1970s. These agents are vesicants – they can cause tissue damage if they extravasate (leak from the vein) or are inadvertently administered into tissue. Anthracycline extravasation injuries, first reported in 1976, were described as ulcers that often progressed to full-thickness skin loss and caused irreversible damage to ­underlying structures, such as tendons, nerves and blood vessels.(1) Later reports noted that these injuries increased in severity over time, did not heal in the usual way, and often required surgical debridement to remove necrotic tissue. In many cases, split-­thickness skin grafting or placement of a skin flap was required.(2)

Anthracyclines are DNA-binding agents. They bind to the cells of healthy tissue when they extravasate and promptly and directly cause cell death. Anthracyclines are retained in the tissue for a long period and are essentially recirculated in the surrounding area, so anthracycline extravasation injuries become larger, deeper and more painful over time.(3,4)

Treatments and antidotes
Since the mid 1970s researchers have studied ­various treatments and antidotes for ­managing ­anthracycline extravasations, including topical ­cooling, saline ­lavage and suction, hyperbaric ­oxygen, topical negative pressure, growth factors, free-radical scavengers (eg, dimethyl sulfoxide [DMSO], alpha-tocopherol [vitamin E], Ginkgo biloba extract), and pharmacological agents (eg, ­diphenhydramine, sodium bicarbonate, ­corticosteroids, heparin, ­lidocaine, dexrazoxane and ­others).(3–6) Until recently, topical application of DMSO has been advocated for anthracycline extravasation ­treatment.(5) DMSO application (every six hours for two weeks) ­prevented tissue necrosis in 16 patients in one study and, in another study, only one patient out of 57 treated with DMSO (every eight hours for one week) ­developed necrosis.(7,8) Side-effects of DMSO include mild ­burning and scaling at the extravasation site and breath odour.(7,8)

Recently, dexrazoxane has been advocated for treating anthracycline extravasation.(5) Of the many agents studied, only dexrazoxane was found ­effective in completely preventing tissue ­necrosis in mice injected with doxorubicin.(9) ­Dexrazoxane is a ­catalytic inhibitor and a metal ion ­chelator that ­protects against the free-radical toxicity induced by ­formation of anthracycline-iron ­complexes. ­Additional ­animal studies and anecdotal clinical reports of the ­success of dexrazoxane in ­reducing anthracycline-induced ­tissue injury led to two ­multicentre trials of the safety and efficacy of dexrazoxane (known as SaveneTM in Europe and TotectTM in the USA and ­produced by TopoTarget A/S of Copenhagen, ­Denmark). In the two trials, patients with fluorescence-verified doxorubicin and epirubicin extravasations received Savene for three consecutive days, with a dose of 1,000 mg/m2 administered intravenously (IV) on days 1 and 2 and a dose of 500 mg/m2 administered IV on day three. Savene was given as soon as ­possible and within six hours of the extravasation. None of the 18 evaluable patients in the first study and only one of the 36 evaluable patients in the second had tissue ­necrosis occurrence (overall efficacy 98%). In addition, most of the patients (71%) were able to receive further chemotherapy ­treatment on schedule. Side-effects of Savene included nausea/­vomiting, ­diarrhoea, ­stomatitis, bone-marrow suppression and increased liver enzyme levels. Treatment sequelae included mild pain (19%) and mild sensory disturbances (17%) at the extravasation site.(10)

Although data suggest Savene is a safe and ­effective treatment, the availability of this agent does not negate the need to administer ­anthracyclines carefully. Patients receiving these agents also need to be informed of the risk of extravasation and actions they can take to reduce this, such as ­avoiding arm movement while the anthracycline is being administered and reporting burning or discomfort.

Immediate treatment
If anthracycline extravasation occurs or is ­suspected, anthracycline administration should be halted at once. The IV site should be inspected for ­swelling and redness, and residual ­anthracycline in the IV device should be aspirated using a 1–3 ml syringe.3,4 Topical cooling (using ice packs) is ­recommended and frequently used as initial anthracycline ­extravasation treatment.(3–5) However, when Savene is ­administered, topical cooling should be removed at least 15 minutes before administration.(10) ­Measurement and photographic documentation of the extravasation area is helpful to assess changes over time. Anthracycline extravasations tend to be painful and may require analgesics.(5)

Conclusion
In many cases, anthracycline extravasations are ­preventable. However, they do sometimes occur and must be promptly detected in order to be ­effectively treated. Healthcare providers who ­prescribe, ­prepare or administer these agents need to be aware of advances in treatment of these ­injuries.

References
1
. Rudolph R, Stein R, Pattillo R. Cancer 1976;38:1087-94.
2. Bowers DG, Lynch JB. Plastic Reconstr Surg 1978;61:86-92.
3. Ener RA, Meglathery SB, Styler M. Ann Oncol 2004;15:858-62.
4. Goolsby TV, Lombardo FA. Semin Oncol 2006;33:139-43.
5. Schrijvers DL. Ann Oncol 2003;24 Suppl 3:26-30.
6. Wickham R, Engelking C, Sauerland C, Corbi D. Oncol Nurs Forum 2006;33:1143-50.
7. Olver IN, Aisner J, Hament A, et al. J Clin Oncol 1988;6:1732-5.
8. Bertelli G, Gozza A, Forno GB, et al. J Clin Oncol 1995;13:2851-5.
9. Langer SW, Sehested M, Jensen PB. Ann Oncol 2001;12:405-10.
10. Mouridsen HT, Langer SW, Buter J, et al. Ann Oncol 2006;18:546-50.



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