Houseman in Pharmacy
Hospital Practitioner in Pharmacy
Hospital Practitioner in Haematology
Hospital Practitioner in Pharmacy/
Head of Department
Centre Hospitalier Victor Dupouy
Anthracyclines such as doxorubicin and epirubicin are among the most widely used drugs in cancer treatment. Their use is limited by cardiotoxicity, which is dose-related, cumulative and irreversible. For this reason, a maximum lifetime dose of doxorubicin of 450mg/m(2) has been recommended. When anthracyclines are also used in the treatment of childhood malignant diseases, cardiotoxicity can be unpredictable. In some cases it may not be evident until later in life.
Dexrazoxane (Cardioxane®) is indicated in France to prevent anthracycline cumulative chronic cardiotoxicity (doxorubicin and epirubicin) in patients with advanced or metastatic cancers who have already received an anthracycline.(1)
The cardiotoxicity of anthracyclines is thought to be linked to the generation of free radicals of oxygen, a process that is catalysed by an anthracycline–iron complex. The mechanism of action is explained in the following way: the cardioprotective activity of dexrazoxane results from chelation of free and/or anthracycline-bound ferric ions in the myocardium. As a result, the pool of free iron in the myocardium is reduced and bound iron is displaced from its potentially damaging complexes with anthracyclines, thus preventing the formation of superoxide radicals.(2,3)
Dexrazoxane is given as a slow intravenous infusion (taking about 15 minutes) approximately 30 minutes before administration of the anthracycline, in a dose equivalent to 20 times the milligram equivalent dose of doxorubicin or 10 times the milligram equivalent dose of epirubicin.(4)
In France, this drug is reimbursed only if it is used for the prevention of the cumulative chronic cardiotoxicity related to the use of doxorubicin or epirubicin among patients with advanced and/or metastatic cancers who have already received a treatment regimen that includes an anthracycline.
Dexrazoxane is relatively infrequently prescribed for patients receiving anthracyclines, and the level of prescribing depends on the country, the pathology and doctors.(5) In the haematology ward of our hospital, this drug was not often prescribed because of its high cost and, particularly, because of unlikely interactions with antitumour drugs.(6) After the publication of studies that showed the efficacy of this drug(7,8) and the absence of interactions that reduced the efficacy of antitumour drugs,(9) the patterns of dexrazoxane prescribing changed.
The aim of this study was to analyse the way in which dexrazoxane was being used in the hospital and to formulate local rules for appropriate prescribing of dexrazoxane.
This retrospective study was undertaken from 1 January 2005 to 31 July 2005. Patients who had been prescribed anthracyclines in the haematology department were included. Patients who received anthracyclines in other departments were excluded. Information was gathered from the Pharmacy and Haematology department records. For each patient the following data were collected:
- Pathology: chronic lymphoid leukaemia (CLL), Hodgkin’s disease (HD), non-Hodgkin’s lymphoma (NHL).
- Prognostic factors (according to the international prognostic index [IPI]) to decide on the therapeutic strategy adopted for each patient with lymphoma:
- Patient’s age (under or over 60 years).
- State of health (Eastern Cooperative Oncology Group [ECOG] score).
- Serum lactate dehydrogenase level (a high level indicates cellular multiplication).
- Disease evolution (Ann Arbor classification).
- Extranodal spread.
Advanced age is a bad prognostic factor because elderly patients are less able to tolerate the treatments. It is usual to distinguish patients under 60 years old, those between 60 and 75 years old, and patients older than 75 years. The state of health is assessed using the ECOG score, which runs from 0 to 4 (Table 1).
Forty-nine patients were included in this study (19 female and 30 male). The patients’ characteristics are shown in Table 2. Among these patients, three (6.1%) suffered from CLL. None of them received dexrazoxane. The average age in this group was 60±14 years. Ten patients (20.4%) had HD. The average age of this group was 28±14 years. They all took dexrazoxane. Thirty-six patients (73.5%) had NHL. Only one patient was given dexrazoxane (2.8%). Among the other 35 patients, 16 (45.7%) had bad prognostic factors (aggressive lymphoma, advanced age) and nine (25.7%) could have had dexrazoxane.
Figure 1 shows the distribution of diagnoses. Patients who received dexrazoxane all benefited from treatment from the first administration of anthracycline. In our study, the anthracycline used was always Adriblastine(®) (doxorubicin).
Among the 49 patients included in this study, three (6.1%) suffered from chronic lymphoid leukaemia. Their age (average 60±14 years) and the low rate of survivals explain why dexrazoxane was not prescribed. Indeed, in this group, the risk of death from the effects of chronic lymphoid leukaemia is greater than the risk of death due to cardiotoxicity induced by the anthracyclines (which is diagnosed by the presence of congestive cardiac insufficiency and a reduction in the fraction of ejection of the left ventricle of more than 15%).
Ten patients (20.4%) with HD all took dexrazoxane. Because of their good chances of recovery and age (28±14 years), this group had a high risk of death from anthracycline-induced cardiotoxicity 10–15 years later if they were not treated with dexrazoxane. Among the 36 patients with NHL, nine patients could have benefited from treatment with dexrazoxane because of their age (less than 60 years) and the absence of unfavourable factors.
This work is of interest because it relates to the use of dexazoxane in haematology and, particularly, in HD, NHL and CLL. Other published studies have been concerned with the role of dexrazoxane as a cardioprotector among patients receiving anthra cyclines for breast cancer, soft tissue sarcoma or small-cell lung cancer.(9,11)
However, in order to compile a complete picture of the usage pattern of dexrazoxane, it would be necessary to undertake this kind of study in other departments, such as the oncology department, that also prescribe dexrazoxane. Moreover, this study was retrospective and a prospective study on a larger population would give more complete information.
In our establishment, haematologists decided to widen dexazoxane prescribing and to prescribe it:
- Automatically to patients with HD because of their young age and high chances of recovery.
- To patients with NHL according to the five prognostic factors that make up the IPI:state of health, lactate dehydrogenase level, disease evolution (Ann Arbor classification),age (under or over 60 years) and extranodal localisation.The lower the IPI, the stronger the justification for prescribing dexrazoxane.
- French Agency Of Medical Safety Of Products Of Health. Opinion of the Commission of transparency. Cardioxane 500 mg, lyophilisat for parenteral use. 11 July 2001.
- Wiseman LR, Spencer CM. Dexrazoxane: a review of its use as a cardioprotective agent in patients receiving anthracycline-based chemotherapy. Drugs 1998;56:385-403.
- Hasinoff BB, Schnabl KL,Marusak RA, et al. Dexrazoxane (ICRF-187) protects cardiac myocytes against doxorubucin by preventing damage to mitochondria.Cardiovasc Toxicol 2003;3:89-99.
- Dictionary Vidal, 2006.
- Swain SM, Vici P. The current and future role of dexrazoxane as a cardioprotectant in anthracyclines treatment: expert panel review.Cancer Res Clin Oncol 2004;130:1-7.
- Swain SM, at al. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 1997;15:1318-32.
- Speyer JL, et al. ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. J Clin Oncol 1992;10:117-27.
- Ten Bokkel Huinink WW, et al.ICRF protects against doxorubicin induced cardiomyopathy. Ann Oncol 1992;3:114 (Abstract).
- Cvetkovic RS, Scott LJ. Dexrazoxane: a review of its use for cardioprotection during anthracyclines chemotherapy. Drugs 2005;35:1005-24.
- Salles G, Coiffier B. Malignant non-Hodgkin’s lymphoma of high rank of malignity. Available from: http://medespace.com/cancero/doc/lmnh.htlm
- Lopez M, et al. Randomized prospective clinical trial of high-dose epirubicin and dexazoxane in patients with advanced breast cancer and soft tissue sarcomas. J Clin Oncol 1998;16:86-92.