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Brian B Hasinoff
Faculty of Pharmacy
University of Manitoba
Accidental extravasation injury from the use of the anthracycline anticancer drugs doxorubicin, daunorubicin, epirubicin and idarubicin can be a serious, and occasionally fatal, complication of their use. When there is accidental leakage of the cytotoxic being infused from the vein into the surrounding tissue extravasation injury may occur. The incidence of extravasation injury from cytotoxic drugs has been variously reported to occur at rates of 0.01–6% in adults.(1,2) Anthracycline extravasation injury can initially lead to pain, swelling and redness at the extravasation site. This may progress over a period of days or weeks to tissue necrosis, with large wounds requiring surgical debridement and/or skin grafts.(1,2) Extravasation injury can also lead to impairment of function, infection and delay in the chemotherapy regimen. Accidental extravasation injury may lead to negligence and malpractice lawsuits as a result of incorrect or omission of appropriate intervention.
The use of the anthracyclines is limited by dose-limiting cardiotoxicity.(3) Doxorubicin and other anthracyclines are quinones that can go through redox cycles after enzymatic reductive activation to their free radical semiquinone species.(4) Semiquinone radicals quickly react with oxygen to generate reactive oxygen species such as superoxide anion and hydrogen peroxide.(4) Anthracyclines also strongly bind iron and this complex can catalyse the formation of the extremely reactive and damaging hydroxyl radical in a redox-cycling reaction.(4) The oxidative stress thus produced is thought to be responsible for the cardiotoxicity and it is likely also responsible for extravasation injury.
Dexrazoxane (see Figure 1) is currently licensed in Europe (Cardioxane(™)), the USA and Canada (Zinecard(™)) and in other countries as a cardio‑protective agent to reduce doxorubicin-induced cardio‑toxicity. As a cardioprotective agent dexrazoxane is infused at a dose of 500 mg/m(2) 30 minutes before doxorubicin is infused. Dexrazoxane (Savene(™)) has recently been licensed in Europe for the prevention of anthracycline extravasation injury, and has orphan drug status (Totect(™)) for this use in the USA. Prior to the introduction of dexrazoxane there was little consensus on the way anthracycline extravasation injury should be managed.(5) The most commonly tried treatment has been the application of topical or intradermal dimethylsulfoxide (DMSO) in combination with cooling. There is no published randomised clinical trial to compare the efficacy of various treatments.
Mechanism of action of dexrazoxane
Dexrazoxane can be considered as a neutral prodrug analogue of the metal chelator EDTA (see Figure 1), which is easily permeable to cells, and which, upon hydrolytic metabolism, yields its strongly iron chelating form ADR-925 (see Figure 1). ADR-925 strongly binds cellular iron and removes iron from the iron-anthracycline complex, thus preventing iron-catalysed formation of damaging reactive oxygen species.(4) A second biochemical property of dexrazoxane is that it is a strong inhibitor6 of the catalytic activity of DNA topoisomerase II. While it is possible that the cardioprotective and extravasation protective effects may also be due to its ability to inhibit topoisomerase II, it is difficult to envision a mechanism by which this would occur.
Preclinical and clinical studies
Preclinical studies in a mouse model for the use of dexrazoxane in preventing anthracycline-induced extravasation injury were extremely positive.(7) These studies compared dexrazoxane treatment to several other treatments that have been tried previously in both animals and in the clinic. By comparison, neither DMSO topically applied nor hydrocortisone intralesionally applied were effective in this model. Additionally, and surprisingly, it was shown that DMSO reduced the efficacy of dexrazoxane treatment. Clinical case reports on the use of dexrazoxane in preventing anthracycline extravasation injury also reported positive outcomes.(8,9)
The results of two prospective, multicentre, single-arm, open-label, phase II/III clinical trials (TT01 and TT02) to assess the efficacy of IV dexrazoxane to prevent severe anthracycline-induced extravasation tissue injury have just been published.(10) Secondary endpoints in these studies were established to assess the toxicity and tolerability of dexrazoxane treatment. Assessable patients for inclusion in the studies had to have anthracycline extravasation verified by fluorescence microscopy of biopsied tissue.(10) The single-dosing protocol and treatment schedule that were used in these trials were: dexrazoxane, 1,000 mg/m(2) starting no later than six hours after the incident; 1,000 mg/m(2) after 24 hours; and 500 mg/m(2) the third day.(10) Dexrazoxane was infused in the arm opposite to that of the extravasation incident. The majority of the study population were women with breast cancer. Epirubicin, followed by doxorubicin, were the anthracyclines that most commonly caused extravasation.
Efficacy was measured by the ability of dexrazoxane to prevent the need for surgical resection of the affected tissue.(10) Prestudy clinical experience in Denmark showed that the need for surgery in biopsy-positive anthracycline extravasation was 100%.(10) In the international study (TT02) the need for surgery after anthracycline extravasation, not biopsy-verified, is estimated at 35–50%.(10) The results of the combined studies showed that in 53 of 54 (98.2%) patients assessable for efficacy, the treatment prevented surgery-requiring necrosis.(10) Only one patient (1.8%) required surgical debridement. In the group studied for efficacy 71% of the patients were able to continue their scheduled chemotherapy without postponement. The most common toxicity, which was reversible and manageable and which likely resulted from a combination of the anthracycline chemotherapy and the dexrazoxane treatment, was haematological due to suppression of bone marrow function. Because DMSO was shown to reduce the efficacy of dexrazoxane treatment in a preclinical study,(7) TopoTarget advises,(11) in a special warning and precaution (see Resources), that DMSO should not be used in patients who are administered dexrazoxane to treat anthracycline-induced extravasation.
In summary, preclinical(7) and clinical case reports(8,9) had suggested that dexrazoxane was effective in preventing anthracycline extravasation injury. A larger (54 assessable patients) prospective, open-label, single-arm, multicentre clinical study(10) in patients with anthracycline extravasation has shown that dexrazoxane is an effective and well-tolerated acute treatment for the prevention of anthracycline-induced surgery.