Dexrazoxane

Abstract

Dexrazoxane has been used successfully to reduce cardiac toxicity in patients receiving anthracycline-based chemotherapy for cancer (predominantly women with advanced breast cancer). The drug is thought to reduce the cardiotoxic effects of anthracyclines by binding to free and bound iron, thereby reducing the formation of anthracycline-iron complexes and the subsequent generation of reactive oxygen species which are toxic to surrounding cardiac tissue. Clinical trials in women with advanced breast cancer have found that patients given dexrazoxane (about 30 minutes prior to anthracycline therapy; dexrazoxane to doxorubicin dosage ratio 20: 1 or 10: 1) have a significantly lower overall incidence of cardiac events than placebo recipients (14 or 15% vs 31%) when the drug is initiated at the same time as doxorubicin. Cardiac events included congestive heart failure (CHF), a significant reduction in left ventricular ejection fraction and/or a ≥2-point increase in the Billingham biopsy score. These results are supported by the findings of studies which used control groups (patients who received only chemotherapy) for comparison. The drug appears to offer cardiac protection irrespective of pre-existing cardiac risk factors. In addition, cardiac protection has been shown in patients given the drug after receiving a cumulative doxorubicin dose ≥300 mg/m². It remains to be confirmed that dexrazoxane does not affect the antitumour activity of doxorubicin: although most studies found that clinical end-points (including tumour response rates, time to disease progression and survival duration) did not differ significantly between treatment groups, the largest study did show a significant reduction in response rates in dexrazoxane versus placebo recipients. Dexrazoxane permits the administration of doxorubicin beyond standard cumulative doses; however, it is unclear whether this will translate into prolonged survival. Preliminary results (from small nonblind studies) indicate that dexrazoxane reduces cardiac toxicity in children and adolescents receiving anthracycline-based therapy for a range of malignancies. The long term benefits with regard to prevention of late-onset cardiac toxicity remain unclear. With the exception of severe leucopenia [Eastern Cooperative Oncology Group (ECOG) grade 3/4 toxicity], the incidence of haematological and nonhaema-tological adverse events appears similar in patients given dexrazoxane to that in placebo recipients undergoing anthracycline-based chemotherapy. Although preliminary pharmacoeconomic analyses have shown dexrazoxane to be a costeffective agent in women with advanced breast cancer, they require confirmation. Conclusions: Dexrazoxane is a valuable drug for protecting against cardiac toxicity in patients receiving anthracycline-based chemotherapy. Whether it offers protection against late-onset cardiac toxicity in patients who received anthracycline-based chemotherapy in childhood or adolescence remains to be determined. Further clinical experience is required to confirm that it does not adversely affect clinical outcome, that it is a cost-effective option, and to determine the optimal treatment regimen. The use of anthracyclines is significantly limited by cardiac toxicity, which occurs in 1 to 2% of patients given a cumulative doxorubicin dose < 450 mg/m². This increases to 20 to 40% at cumulative doses >600 mg/m². Children appear to be more susceptible to the cardiotoxic effects of this class of drugs than adults, although toxicity may not become apparent until years after cessation of therapy. Cardiac toxicity is thought to occur principally as a result of oxidative stress placed on cardiac myocytes by reactive oxygen species (generated by the stable complex formed between anthracyclines and iron). Consequently, the ability of free-radical scavengers and metal-chelating agents to reduce cardiac toxicity has been investigated. Dexrazoxane, a cyclic derivative of edetic acid (EDTA), provides cardiac protection from anthracyclines primarily through its metal-chelating activity. The hydrolysis products of dexrazoxane have been shown to chelate both free and bound intracellular iron, including iron that is bound in anthracycline complexes, thereby preventing the generation of cardiotoxic reactive oxygen species. The hydrolysis products are thought to be responsible for most of the activity of the drug. The cardioprotective activity of dexrazoxane has been demonstrated in animal models of anthracycline-induced cardiac toxicity. Dexrazoxane administration was associated with a significant reduction in the number of cardiac lesions and increased survival after toxic doses of anthracyclines. In studies in beagle dogs and rats, the drug appeared more effective when administered prior to or simultaneously with the anthracycline. In addition, delayed administration until after the sixth dose of doxorubicin was less effective than administration at the time of the initial doxorubicin dose (in contrast, delayed administration did not appear to reduce dexrazoxane's cardioprotective effect in patients). Studies in patients receiving anthracycline therapy for cancer indicate that the pharmacokinetic properties of dexrazoxane fit a 2-compartment model with first-order elimination kinetics. Absorption is linear within the dose range 60 to 900 mg/m²: the mean peak plasma concentration is 36.5 mg/L after a 15-minute intravenous infusion of dexrazoxane 500 mg/m². The distribution half-life is about 15 minutes and the steady-state volume of distribution has been estimated to be about 1.1 L/kg. Protein binding is usually 2) are generally unchanged when the drug is administered 15 to 30 minutes after dexrazoxane (600 o 900 mg/m²) intravenous infusion. However, the properties of epirubicin may be altered by dexrazoxane when the drug is administered at doses ≥100 mg/m². Clinical trials have shown dexrazoxane to significantly reduce the incidence of cardiac toxicity in patients receiving anthracycline-based chemotherapy for advanced breast cancer. Cardiac events indicative of cardiac toxicity included congestive heart failure (CHF), a reduction in the resting left ventricular ejection fraction (LVEF) to 2)-induced cardiac toxicity was 15 and 14% in patients given dexrazoxane (500 mg/m² about 30 minutes prior to each dose of the anthracycline) versus 31% in both groups of placebo recipients. CHF occurred in 15% of placebo recipients but in no patients treated with dexrazoxane in one of these studies. Where reported in comparative studies, clinically relevant reductions in LVEF were less common in patients treated with dexrazoxane than in dexrazoxane-untreated control patients or placebo recipients. In most studies, dexrazoxane therapy was started at the same time as anthracycline therapy; however, it may also be cardioprotective when administration is delayed until a cumulative dose of doxorubicin ≥300 mg/m² has been given (incidence of cardiac events 60% in patients given placebo throughout (for up to 13 cycles of chemotherapy) versus 25% in patients initially given placebo (for 6 cycles of chemotherapy) then switched to dexrazoxane according to protocol amendment). The extent of cardiac protection offered by dexrazoxane appeared similar in patients with or without pre-existing cardiac risk factors. Dexrazoxane did not affect the clinical outcome of anthracycline therapy in most studies. However, the largest study did show a significantly lower rate of tumour response to doxorubicin therapy in patients given dexrazoxane versus that in placebo recipients (46.8 vs 60.5%). Other studies (including one by the same investigators) have failed to show any detrimental effect of dexrazoxane on the antitumour activity of anthracyclines. The cardiac protection offered by dexrazoxane permits the administration of doxorubicin beyond standard cumulative doses. However, it remains unclear whether this will prolong the time to disease progression or the overall survival duration. While there was a trend towards prolonged survival in dexrazoxane recipients in most studies, the difference did not reach statistical significance (except in a retrospective analysis of patients given placebo or placebo followed by dexrazoxane as a result of protocol amendment). Preliminary results (from small nonblind studies) indicate that dexrazoxane is also an effective cardioprotective agent in children and adolescents receiving anthracycline-based chemotherapy for a range of malignancies: the incidence of cardiac toxicity was 22 vs 67% in dexrazoxane-treated and -untreated patients in one study. Further investigation in this high-risk patient group, with regard to long term benefit, is warranted. Available data from clinical trials in women with advanced breast cancer indicate that coadministration of dexrazoxane with anthracycline-based chemotherapy does not compromise tolerability in most patients. As expected, haematological toxicity was common in all treatment groups, but was generally more frequent in patients given dexrazoxane than in control groups (either placebo or no additional treatment). In comparisons with placebo, the incidence of severe leucopenia [Eastern Cooperative Oncology Group (ECOG) grade 3/4] at nadir was significantly higher in dexrazoxane recipients (78 vs 68%; p < 0.01). However, the incidences of severe granulocytopenia and thrombocytopenia did not differ significantly between treatment groups. The incidence and nature of other adverse events including vomiting, mucositis, infection, fever with neutropenia, alopecia, diarrhoea, fatigue, anaemia, haemorrhage, sepsis and stomatitis were similar between treatment groups. Pain on injection was more common with dexrazoxane than with placebo, whereas severe nausea (ECOG grade 3/4) appeared more common with placebo in comparative trials. Limited data indicate that the drug has similar tolerability in children and adolescents to that observed in women with advanced breast cancer. Pharmacoeconomic analyses [based on data from a retrospective study of patients with breast cancer given placebo for up to 13 cycles of chemotherapy or placebo for 6 cycles then dexrazoxane (as a result of protocol amendment in 2 phase III studies)] indicate that the administration of dexrazoxane to prevent anthracycline-induced cardiac toxicity was cost-effective. Dexrazoxane cost $US5662 per cardiac event prevented and $US12 992 per CHF event prevented (based on 1995 costs). It was also found to cost $US2809 per life-year gained; however, survival data used in this analysis require confirmation. The investigators concluded that dexrazoxane compared well in terms of cost-effectiveness with other medical interventions in routine use in the US and Canada, including invasive cardiac monitoring to prevent heart failure. For protection against anthracycline-induced cardiac toxicity, the recommended dexrazoxane to anthracycline dosage ratio is 10: 1 in the US (i.e. 500 mg/m² for a 50 mg/m² doxorubicin dose) or 20: 1 in Europe. Dexrazoxane should be administered by intravenous infusion (slow push or rapid drip infusion), starting approximately 30 minutes before anthracycline infusion. In Europe, dexrazoxane should be initiated at the same time as anthracycline therapy whereas in the US delayed administration until a cumulative dose of 300 mg/m² doxorubicin is given is recommended. The maximum dose given in any cycle should not exceed 1000 mg/m². Dexrazoxane may potentiate haematological toxicity induced by chemotherapy or radiation; thus monitoring of haematological parameters is recommended. The drug should not be given to pregnant or breast-feeding women, and caution is required in patients with renal or liver impairment.