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Published on 24 March 2010

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Dexrazoxane in anthracycline extravasation

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Anthracyclines are used as cytotoxic agents in a wide range of malignant diseases. The EMEA approval in July 2006, made a potent drug, dextrazoxane, available for the treatment of anthracycline extravasation and the prevention of tissue necrosis

Timo Behlendorf
Karin Jordan
Hans-Joachim
Schmoll
Clinic for Internal
Medicine IV
Oncology/Haematology
Department for Internal
Medicine
University Hospital Halle
Halle, Germany

Anthracyclines are used in a wide range of malignant diseases such as breast cancer, leukaemia and sarcomas and are extremely significant in cytotoxic cancer chemotherapy. Extravasation of anthracyclines is one of the most frightening complications of intravenous chemotherapy and the treatment of this complication is an enduring challenge for haematologists, oncologists and other physicians dealing with cytotoxic chemotherapies.[1]

Different types of treatment of anthracycline extravasations such as hyperbaric oxygen therapy, surgical intervention or local application of dimethylsulphoxide, an apolar aprotic solvent, have been performed. However, the outcome of these treatment approaches was not satisfactory in most cases.[2-4]

The approval of Savene (dextrazoxane) in July 2006 provided Europe with a new tool for the treatment of anthracycline extravasations. Each Savene box contains 10 vials of dexrazoxane powder (10 x 500mg each) and 3 bags of Savene diluent (3 x 500ml each) for infusion. In September 2007 the US Food and Drug Administration approved Totect (dexrazoxane) and provided a new tool for the treatment of extravasation of iv anthracycline chemotherapy.[5,6] This article will focus on dexrazoxane, especially its trials and its clinical implications.

Anthracycline extravasation
The incidence of extravasation is estimated at 0.1% to 6% of all applications of cytotoxic chemotherapy.[7,8] Cytotoxic agents can be divided into three different groups according to their damaging potential:

  • Non-vesicant drugs seldom cause tissue damage if extravasated.
  • Irritant drugs cause local pain and can induce local inflammatory reaction when applied to the vessel surrounding tissue.
  • Vesicant drugs have the ability to induce tissue destruction, presenting with blisters and necrosis in the affected area.

Table 1 shows examples.

General treatment recommendations in case of an extravasation are:

  • Immediate discontinuation of infusion/injection.
  • Slow aspiration from the venous access device with a 5ml syringe.
  • Avoid compression of the affected area.
  • In the development of blisters, attempt aspiration with a 1ml syringe and a thin subcutaneous needle.

Specific antidotes are only available for a few substances, for example, hyaluronidase for vincalkaloids or dexrazoxane for anthracyclines.[9]

Dexrazoxane
The approval for Savene (dexrazoxane) was based on efficacy studies conducted in Europe to evaluate the drug as a post-extravasation treatment.[10,11] In addition, several case reports concerning the successful treatment with dexrazoxane had been published.[12,13] In each study, the observed treatment, frequency and severities of tissue damage appeared to be reduced significantly by dexrazoxane infusions administered after anthracycline extravasation.

Structure and possible mechanisms of action
Dexrazoxane is a white powder which is hardly soluble in water. Different buffer substances such as phosphate or borate improve solubility. Its melting point is 194°C.[14] The systematic name (IUPAC) of dexrazoxane is 4-[(2S)- 2-(3,5-dioxopiperazin-1-yl)propyl]piperazine-2,6-dione. The chemical structure of dexrazoxane is shown in Figure 1. Dexrazoxane is a non-charged pro drug of the chelating agent EDTA. This attribute is suspected to be one of the possible mechanisms of action.

By forming complexes with metal ions, dexrazoxane reduces the oxidative activity of complexes formed by anthracyclines and metal ions in the tissue.

Although this mechanism appears to be a possible means of action of dexrazoxane, Langer et al could not confirm this theory with other chelating agents such as EDTA or the hydrolytic degradation product of dexrazoxane ADR 925 applied intralesionally or sys-temically after subcutaneous application of anthracyclines in mice.[15]

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Another way of explaining how dexrazoxane works is the reversible inhibition of topoisomerase II, a  enzyme necessary for cell division.[16] Other mechanisms may be present in the inhibition of topoisomerase II such as merbarone. However, merbarone did not result in prevention of tissue damage after subcutaneous injection of anthracyclines in mice.[15] The complete mechanism of action is still unknown.

Pharmacokinetics of dexrazoxane

The pharmacokinetics of dexrazoxane have been studied initially in patients with advanced cancer with normal renal and hepatic function. Distribution and degradation of dexrazoxane can be described as an open two-compartment model with first-order elimination. It is not bound to plasma proteins and urinary excretion is the primary way of elimination.[14]

The disposition kinetics of dexrazoxane are dose-independent, as shown by linear relationships between the area under plasma concentration-time curves and administered doses ranging from 60 to 900mg/m2.

Drug interactions
There were no significant changes in the pharmacokinetics of doxorubicin (50mg/m2) and its predominant metabolite, doxorubicinol, in the presence of dexrazoxane (500mg/m2) in a crossover study in cancer patients.[17]

Development as a drug for anthracycline extravasation
The first clues for the activity of dexrazoxane in extravasation of anthracyclines appeared in 2000. Langer et al found a significant reduction in tissue ulcerations after experimental anthracycline extravasation in mice after the systemic administration of dexrazoxane.[15]

After the first experimental applications in humans occurred, Langer et al published two cases of anthracycline extravasation following a successful intravenous treatment with dexrazoxane. At this time dexrazoxane was only approved for the prevention of anthracycline-induced cardiotoxicity. In both patients with anthracycline extravasation no surgical intervention was necessary and the extravasations restored without sequela,[18] whereas a progression of anthracycline extravasation to tissue necrosis and ulceration without treatment is denoted in the literature with rates of up to 50%.[19]

Encouraged by this promising data, Mouridsen et al. designed two prospective trials called TT01 and TT02.10 TT01 was performed in Denmark, recruiting patients from 17 centres, while TT02 was performed with the participation of 36 centres in Germany, The Netherlands, Italy, Poland and Denmark. Both trials were conducted as phase II/III multicentre trials.

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The main inclusion criteria for both studies were:

  • Age >18.
  • ECOG Performance Status >2.
  • Pathologically-confirmed anthracycline extravasation (fluorescence microscopy). The main exclusion criteria were:
  • Pre-existing elevations of liver enzymes (>3-fold).
  • Haematological impairment (>CTC 2).
  • Known dexrazoxane allergy.
  • Possible extravasation of other necrotising agents such as vinca-alkaloids.

Treatment with dexrazoxane had to be initiated as soon as possible, but no longer than 6 hours after the anthracycline extravasation. Administration of dexrazoxane was performed as an infusion to the opposite arm of the extravasation with a dose of 1000mg/m² on day 1 and 2 and 500mg/m² on day 3.

Primary endpoints were the need for surgical intervention after extravasation and the development of sequelae and secondary endpoints were postponement of the scheduled chemotherapy and the assessment of toxicity and tolerability of dexrazoxane when used after anthracycline extravasation.

In the TT01 trial, 18 patients were assessable for efficacy and 23 patients for safety data. The TT02 trial recruited 36 patients assessable for efficacy and 57 for safety data.

In summary, dexrazoxane showed high activity in the prevention of tissue necrosis and the need for surgical intervention. In TT01 none of the patients had to undergo surgery while in TT02 only one out of 36 patients (2.8%) needed further surgical treatment. Treatment delay resulted in six patients (33%) in TT01 and in 10 patients (27.8%) in TT02, with a median of 10 days delay.

Sensory disturbances appeared in 16.7% of patients, skin atrophy in 9.3%, pain at the extravasation site was found in 18.5%, disfigurement in 2.8% and limitation of movement in 5.6% of the trial patients. Grade 4 toxicity could not be detected in terms of phlebitis, fever, wound infections, mucosal reactions or nausea and vomiting.

Concerning safety, haematological side-effects were the ones most frequently detected. A decrease in the white blood count or neutrophils grades 2-4 was found in 72.5% and 61.5% of the treated patients, respectively. Other paraclinical toxicities were principally elevations of liver function tests, especially
aminotransferases and bilirubin, but no grade 4 toxicity was observed. It has to be kept in mind that the patients enrolled in these studies were cancer patients undergoing cytotoxic chemotherapy who were associated with possible haematological and liver toxicity.

Overall, Mouridsen et al. provided evidence that the administration of dexrazoxane after occurrence of an anthracycline extravasation is an effective and safe agent for the prevention of tissue necrosis, and it is able to reduce the need for surgical intervention after extravasation of anthracyclines.[10]

Administration of dexrazoxane
According to the doses used in the TT01 and TT02 trials the recommended and approved dosage of dexrazoxane for the treatment of anthracycline extravasation is shown in Table 2. The first administration should take place as soon as possible after the extravasation, not exceeding 6 hours afterwards. Dexrazoxane should be administered as an intravenous infusion over one to two hours in a large calibre vein in an extremity/area other than the one affected by the extravasation.[4] Cooling procedures such as dry cold packs should be removed from the area at least 15 minutes before the infusion in order to allow sufficient blood flow in the extravasation area. Treatment on day 2 and day 3 should start at the same time (+/-3 hours) as on the first day.

A dose reduction of 50% of dexrazoxane is necessary in patients with creatinine clearance values <40ml/min.

As dimethyl-sulphoxide also showed little activity in the topical treatment of anthracycline extravasation, the theoretical idea of combining topical DMSO and systemic dexrazoxane is an understandable one.[3] Unexpectedly, the combination of topical DMSO and systemic dexrazoxane lessened the prevention rate of tissue necrosis in an extravasation model in mice.[20] The utilisation of DMSO and dexrazoxane in combination, therefore, is obsolete.

Local cooling is a common practice after extravasation injuries. For the patient, application of cold covers lead to pain relief. To ensure a sufficient blood perfusion in the area of extravasation, cold covers should be removed at least 15 minutes before the infusion of dexrazoxane. Cooling in combination with systemic dexrazoxane should therefore not be performed.

Special fields of application
Because of their reduced cardiotoxic potential, liposomal anthracyclines have become a widespread application form of intravenous chemotherapy.[21] Extravasations with liposomal anthracyclines evolve generally in a milder form than extravasations with conventional anthracyclines because of the retarded liberation of the toxic agent.[22,23] A theory for the reduced tissue damage of liposomal anthracyclines is the evacuation of the liposomal drug via the lymphatic system which thereby prevents local damage.[24]

In the TT01/TT02 studies only one patient was treated with a liposomal formulation of anthracycline. This patient did not respond as well as the patients treated with conventional anthracycline to the dexrazoxane treatment.[10] Further investigations have to be performed to explore the possible use of dexrazoxane in extravasations with liposomal anthracyclines.

Conclusions
Anthracycline extravasation is still a therapy and health threatening complication of intravenous chemotherapy. With the development of dexrazoxane, a potent agent for reducing the damage of anthracycline extravasation has been established. The promising data of the two prospective trials TT01 and TT02 are encouraging. However, the introduction of this new antidote needs to be audited for its efficacy in practice and further research work should be performed the better to refine and develop its use.

Centres treating patients with i.v.-anthracyclines should have fast access to dexrazoxane to provide optimal treatment without delay in case of an anthracycline extravasation.

Evidence consensus-based guidelines for the treatment of chemotherapeutic agent extravasation are difficult to formulate due to a lack of randomised studies.

However, the Supportive Therapy Group (ASORS) within the German Cancer Society (Deutsche Krebsgesellschaft) developed such practical guidelines for the management of extravasation, including the use of dexrazoxane, and represents one of the early guidelines in this area.

References
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2. Monstrey SJ et al. Ann Plast Surg 1997;38:163-68.
3. Dorr RT. Blood Rev 1990;4:41-60.
4. Wengstrom Y, Margulies A. Eur J Oncol Nurs 2008;12:357-61.
5. Kane RC et al. Oncologist 2008;13:445-50.
6. Parsons JL, Jr. Clin J Oncol Nurs 2007;11:789.
7. Cox K et al. Med J Aust 1988;148:185-89.
8. Schrijvers DL. Ann Oncol 2003;14 (Suppl 3):iii26-30.
9. Goolsby TV, Lombardo FA. Semin Oncol 2006;33:139-43.
10. Mouridsen HT et al. Ann Oncol 2007;18:546-50.
11. Ward MS. Clin J Oncol Nurs 2007;11:613; author reply 613.
12. El-Saghir N et al. Lancet Oncol 2004;5:320-21.
13. Held-Warmkessel J. Nursing 2007;37:72.
14. Jordan K et al. Ther Clin Risk Manage 2009;5:361-66.
15. Langer S. Ann Oncology 2001;12:405-10.
16. Langer S. Cancer Chemother Pharmacol 2006;57:125-28.
17. Chow WA et al. Cancer Chemother Pharmacol 2004;54:241-48.
18. Langer S. J Clin Oncology 2000;18:3064.
19. Kaehler KC et al. J Dtsch Dermatol Ges 2008;3:150-59.
20. Langer SW et al. Cancer Chemother Pharmacol 2006;57:125-28.
21. Rahman et al. Int J Nanomedicine 2007;2:567-83.
22. Cabriales S et al. Oncol Nurs Forum 1998;25:67-70.
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