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Published on 1 July 2007

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Savene(TM) (dexrazoxane): an effective nonsurgical treatment for anthracycline extravasation

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Jan Buter
MD PhD

Medical Oncologist

Department of Medical Oncology
Free University Medical Center
Amsterdam
The Netherlands

E: J.Buter@vumc.nl

Extravasation with anthracyclines – cytotoxic agents belonging to the vesicant group – is a feared and serious complication of chemotherapy administration. The condition is rare and the clinical picture is heterogeneous, resulting in a number of problems in diagnosing an extravasation on clinical grounds only, especially in the case of smaller extravasations.

The severity of such an accident depends on the anthracycline itself, the location of the ­extravasation and the amount of drug that reaches the tissue. The incidence of accidental extravasation injury with cytotoxic drugs has been variously reported in the literature to range between 0.01% and 6% in adults.(1,2)

A rough estimate is that the incidence of extravasations due to anthracyclines is 0.1–1.0%.
Four treatment approaches have been used: ­conservative observation alone, surgery, nonpharmacological methods and pharmacological methods. None of the nonsurgical methods has proved to be effective in biopsy-verified cases and many patients end up with serious sequelae after the incident, either from the extravasation itself or from the surgery. The progression rate to ­ulceration of the induration after extravasation from a ­peripheral venous access is 25–50% and occurs after one to four weeks (see Figure 1).(3–7)

[[HPE33_fig1_38USE]]

Extravasations from a central venous catheter (CVC) often pose special problems in treatment due to the site of the catheter being embedded. This may result in a large extravasation occurring before the accident is noticed − a fact which underlines the need for an effective systemically administered
antidote.(8)

Surgical treatment
The extent of the necessary surgical debridement in a case of a CVC extravasation is made clear from Figure 2. Extravasation results in decreased ­quality of life for patients, as it causes hospitalisation, long-term pain, contractures, dystrophy and loss of function of the affected limb, even when surgically treated.(6,8–13)

[[HPE33_fig2_39USE]]

Surgical interventions may also result in infection both at the donor site used to obtain the graft for the ­extravasation area and at the area itself. This may delay or even stop ­scheduled chemotherapy for the underlying cancer, which again may impact the prognosis of the underlying disease. Disfigurement resulting from an extravasation may also cause psychological problems for the patient, just as the treatment itself may make it difficult for the patient to ensure that they can hold down a job effectively (Figure 3).

[[HPE33_fig3_39USE]]

A new antidote
The new ­systemic antidote, Savene(TM) (dexrazoxane), is theonly proven and approved treatment for anthracycline extravasation.(14) This has proved to be an effective and well-tolerated acute treatment in anthracycline-induced extravasation, with only one out of 60 assessable patients ­requiring surgical resection (1.7%).(15) The daily ­dosage of Savene is 1,000 mg/m(2) IV, starting no later than six hours after the incident, 1,000 mg/m(2) after 24 hours and 500 mg/m(2) on the third day.

Case histories
Reports on three different cases in patients with breast cancer in whom Savene treatment was ­successful are presented below.

Case 1
A 58-year-old patient who was treated with ­epirubicin experienced an extravasation in a forearm, size 7 x 11 cm. The lesion was verified by fluorescence microscopy. Recommended treatment with Savene was started within five hours. The extravasation resolved without surgery, and the patient was able to resume chemotherapy after a one-week delay. She was without sequelae at three months.

Case 2
A 45-year-old patient had an ultrasonically ­verified doxorubicin extravasation in the chest wall. Estimated volume was 149  mg. Again, the recommended treatment with Savene was started within five hours. This patient also recovered without ­surgery, was able to resume chemotherapy after a one-week delay, and had no sequelae at three months.

Case 3
A 60-year-old patient had a biopsy-verified ­epirubicin extravasation in her right hand and received ­recommended Savene treatment, starting within six hours. Swelling and redness persisted in an area of 1 x 1.5 cm until day 18, but full recovery was obtained at day 28. Her antineoplastic therapy ­continued without delay.

The only side-effects reported were those that would be expected from anthracycline chemotherapy and consisted of transient elevation of transaminases (twice the upper level of normal for less than seven days) and transient leucopenia (Common Toxicity Criteria grade 2), in cases 1 and 2. No side-effects were observed in case 3.

All the available clinical evidence suggests that Savene has a favourable tolerability profile.

Conclusion
Anthracyclines are highly potent anticancer drugs for treating solid tumours as well as lymphomas and leukaemia. Anthracycline extravasation can result in a lifelong handicap, and as it is not possible to eliminate the risk completely, it is important to retain Savene in stock, as treatment must be initiated as soon as ­possible or within six hours of the extravasation.

References
1. J Pediatr Oncol Nurs 2000;17:135-48.
2. Ann Oncol 2003;14 Suppl 3:iii26-30.
3. Oncol Nurs Forum 2000;27(3):1-12.
4. Cancer 1977;40:2053-6.
5. Ann Plast Surg 2002;49:369-74.
6. J Surg Oncol 1983;23:259-62.
7. Ann Plast Surg 1987;19:323-9.
8. Cancer 1982;49:1796-9.
9. Eur J Cancer 1993;12:1712-4.
10. Plat Reconstr Surg 1985;75:397-402.
11. Hand Surg 1983;8:32-8.
12. Ann Oncol 2007;18:546-50.
13. Ann Plast Surg 1994;32:39-44.
14. HPE 2007;32:69-70.
15. Proc Am Soc Clin Oncol 2007;25:2555.

Resource
TopoTarget Savene™ information website for healthcare professionals
W: www.savene.com



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