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Dexrazoxane for anthracycline extravasations: a new standard of care?
The drug's approval was based on two European studies.
In September 2007, the FDA approved dexrazoxane hydrochloride injection for the treatment of extravasation resulting from intravenous anthracycline chemotherapy.
Dexrazoxane (Zinecard, Pfizer) has been available since 2002 as a cardioprotective agent indicated for reducing cardiomyopathy associated with doxorubicin chemotherapy. However, based on data from preclinical studies in mouse models and small clinical case reports suggesting that dexrazoxane could prevent anthracycline induced tissue necrosis, studies evaluating its use as an antidote to anthracycline extravasations were conducted.
FDA approval of dexrazoxane hydrochloride (Totect, TopoTarget A/S) was based on two prospective, open-label, single-arm, multicenter studies conducted in Europe. Researchers tested whether IV administration of dexrazoxane hydrochloride could prevent tissue damage and reduce the need for surgical intervention in patients following anthracycline extravasation.
Patients were eligible if they received single-agent anthracycline IV — usually as part of combination chemotherapy — and developed extravasation symptoms including pain, swelling, blistering or redness near the infusion site. Anthracycline extravasation was confirmed by positive fluorescence microscopy of tissue biopsies. Dexrazoxane hydrochloride was administered as soon as possible and no later than six hours after extravasation, with treatment repeated 24 and 48 hours later (total of three doses).
Eighty patients were enrolled in these two studies and 57 were eligible for analyses. Eligible patients were required to have skin biopsies demonstrating fluorescence and had to receive the first dexrazoxane hydrochloride dose within six hours of extravasation. The most common cancer diagnoses were breast cancer and lymphoma. The most common anthracyclines administered were epirubicin and doxorubicin. Peripheral sites of extravasation included the forearm (63%), hand (21%) and antecubital area (11%). Five percent of patients received the anthracycline via a central venous access device.
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Of the 57 evaluable patients in which extravasations were confirmed, one required surgery after dexrazoxane hydrochloride treatment. Mild pain, sensory disturbances and/or skin atrophy were the most frequent sequelae in the patients who did not require surgery. None of the patients with central venous access devices required surgical intervention.
Adverse effects consisted mainly of injection site reactions, nausea/vomiting and wound infections. Dexrazoxane has known myelosuppressive effects, and hematologic toxicity was observed secondary to the additive effects with chemotherapy. Leukopenia, neutropenia, anemia and thrombocytopenia, as well as reversible elevations in liver enzymes occurred.
Dexrazoxane is both a topoisomerase II inhibitor and an iron chelator. The mechanism by which it reduces tissue injury following anthracycline extravasation is unknown. However, postulated mechanisms include antioxidant effects that may occur in local tissues and counteract free radical tissue destruction.
Dosage and administration
Dexrazoxane hydrochloride is provided as a single-patient anthracycline extravasation kit consisting of 10 vials of dexrazoxane hydrochloride powder (500 mg dexrazoxane) and 10 vials of diluent. It should be given within six hours after extravasation. It is administered as an IV infusion in a liter of normal saline through a large vein in a location other than the site of extravasation, once daily for three consecutive days.
The dose is 1,000 mg/m2 given on days one and two, and 500 mg/m2 given on day 3 (up to a maximum body surface area of 2 m2). A 50% dose reduction is recommended in patients with a creatine clearance less than 40 mL/min. In the clinical trials, acute aspiration of the anthracycline from the existing IV line was recommended if possible. Topical cooling was also permitted, however it was discontinued at least 15 minutes prior to and during dexrazoxane hydrochloride administration to allow sufficient blood flow to the area of extravasation. Other topical treatments were not allowed.
Standard management
Currently, uniform consensus on standard management for anthracycline extravasations does not exist. Early surgery with debridement is an option for limiting the tissue damage from extravasations, but requires an experienced and available plastic surgery team to make this a standard management approach. Data to support the use of nonsurgical local treatments and antidotes for management of vesicant extravasations has been largely empirical and controversial since much of the existing literature consists of animal studies, anecdotal case reports and small uncontrolled trials. In addition, equivocal results have been reported from studies investigating several antidotes, including topical steroids, topical dimethyl sulfoxide, topical cooling and/or saline lavage with suction. Of these, only topical cooling has become routinely incorporated into standard clinical practice.
Due to the emergent and infrequent nature of this complication and the lack of standard, proven, effective management strategies, clinical trials investigating new treatments are not able to be randomized or controlled. Also, most studies investigating antidotes for anthracycline extravasations rely on clinical assessment alone to determine whether an extravasation has occurred. A strength of the dexrazoxane hydrochloride data is the biopsy-confirmation of extravasations. However, this also complicates comparisons with historical data that lack this confirmation. Therefore, it remains largely unknown as to whether the patients would have had similar outcomes with other management strategies given similar clinical scenarios.
Regardless of the anthracycline dose administered, dexrazoxane hydrochloride is given at a fixed dose based on body surface area, and not the 10-to-1 dose ratio of dexrazoxane–doxorubicin as indicated for reducing cardiotoxicity. Thus whether lower doses or other schedules of dexrazoxane hydrochloride could be effective for treatment of extravasations is unknown. Given the differences in relative potency and cardiotoxicity of specific anthracycline agents, whether different doses of dexrazoxane hydrochloride may be given for extravasations with each specific anthracycline is also uncertain (Table 1). As recommended by the FDA, further postmarketing pharmacokinetic analyses and the relationship between dexrazoxane concentrations and clinical outcomes — both extravasation-related and toxicity related — should be explored.
The effect of dexrazoxane on the cancer itself is currently unknown. Theoretically, antioxidants could potentially negate the antitumor effects of the anthracyclines. Therefore, if dexrazoxane hydrochloride is used for treating an extravasation, then whether the anthracycline dose or the entire cycle of chemotherapy should be re-administered is another question that remains unanswered. In potentially curative settings, clinicians may need to consider repeating the anthracycline dose to ensure the patient has received optimal treatment. The cost of this additional therapy should also be considered in any future pharmacoeconomic analyses.
Dexrazoxane hydrochloride is only effective for treatment of anthracycline (nonliposomal) extravasations, and is not indicated for extravasations due to other chemotherapy vesicants.
Dexrazoxane hydrochloride has an expiration dating period of 18 months, and costs $14,750 average wholesale price per single-patient kit. The company, TopoTarget USA Inc., has a one-time replacement kit policy for the original unused kit that will replace the product at no charge if the first kit expires before use, as outlined in a license agreement and limited warranty contract. Thereafter, institutions are required to pay for all replacements. The manufacturer has also applied for a Centers for Medicare and Medicaid Services J-code for billing and reimbursement.
Rate of extravasations
Chemotherapy extravasations are relatively rare, occuring in 1% to 7% of cases. It is difficult to accurately measure the incidence of extravasations, but it has more than likely decreased since the introduction of guidelines for administration of vesicants and the widespread use of central venous access devices. The cost of treating an extravasation is unknown, but direct and indirect medical costs may exceed several hundred thousand dollars. The cost of dexrazoxane hydrochloride is a fraction of this. However, the pharmacoeconomics of stocking the product could be considerable if there is low use and the cost of re-administering chemotherapy may also have to be considered.
The availability of other, less expensive forms of dexrazoxane (generic and Zinecard) raises the question of whether these products can be used at a lower cost with similar outcomes. The concentration of the supplied sodium lactate diluent does differ between products. In the registration studies for dexrazoxane, there was initially a higher rate of superficial phlebitis when dexrazoxane was first given at the doses used for extravasation. This adverse event was diminished in subsequent studies after buffer changes to the solvent were made. This newer formulation is employed with the brand Totect (TopoTarget A/S). Dexrazoxane hydrochloride is the only product with the indication for treatment of anthracycline extravasations that also has a U.S. patent for this method of use. Based on this patent, substitution of other forms of dexrazoxane for anthracycline extravasation treatment constitutes patent infringement. The medical and legal implications of this dilemma are unclear at this time.
Prevention is the primary goal for protecting patients from extravasation injury due to anthracyclines. The use of specific guidelines for infusion and administration through a CVAD appear to reduce the incidence of vesicant extravasations (Table 2). However, accidental extravasations still occur.
The use of antidotes for anthracycline extravasations has been controversial. Clinical trial data suggest that dexrazoxane hydrochloride is an effective treatment of anthracycline extravasations, and provides a therapeutic option for a rare, but potentially damaging adverse effect of chemotherapy. Whether national extravasation guidelines will accept this agent as a standard remains to be seen. However, there appears to be a number of important unanswered questions.
For more information:
- Janet Espirito, PharmD, BCOP, is a clinical pharmacy specialist and Laura B. Michaud, PharmD, BCOP, FASHP, is manager of clinical pharmacy services at The University of Texas M.D. Anderson Cancer Center.
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