The future for dexrazoxane in Europe

Carl Booth  Lead Pharmacist for Cancer Services and Clinical Trials, Airedale NHS Foundation Trust, based at Airedale General Hospital in West Yorkshire, UK.

Jean-Claude Gentet  Paediatric Oncologist, Department of Paediatric Oncology, Hôpital des Enfants, Marseille, France

Steffi Künne  Oncology Pharmacist, Central Pharmacy, St Johannes Hospital Dortmund, Germany

Sandra Melville  Clinical Pharmacy Manager and past Chair of the Scottish Pharmacy Board, Lorn & Islands, Oban, UK

Julie Mycroft  Principal Pharmacist Paediatric Oncology, Royal Marsden NHS Foundation Trust, Sutton, UK

Xavier Pivot  CHU Jean Minjoz, 1 Boulevard Fleming, 25030 Besançon Cédex 03, France

María José Tamés Hospital Pharmacy Specialist, Assistant Manager Pharmacy Department, Onkologikoa Foundation, San Sebastian, Spain

Rainer Trittler  Clinical Pharmacist, University Hospital Freiburg, Head of the Analytical Section, Freiberg, Germany

Marta Trojniak  Pharmacist, Oncology Pharmacy Department, Veneto Institute of Oncology, IRCCS, Padua, Italy

Bruce Burnett (Meeting Chair)  Senior Lecturer Hospital Teacher Practitioner, University of Wolverhampton, Wolverhampton, UK

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Dexrazoxane hydrochloride (Cardioxane®) is an analogue of ethylene diamine tetra-acetic acid, which protects the heart against the cardiotoxic effects of anthracylines, such as doxorubicin and epirubicin. While anthracyclines are among the most efficient chemotherapeutic agents in both adults and children in the treatment of numerous malignancies, their use is limited by this dose-dependent cardiotoxicity.

How anthracyclines damage heart muscle is imperfectly understood, but one theory is that the generation of free radicals by anthracycline–iron complexes results in oxidative stress on the cardiac muscle, which is susceptible due to a lower level of protection enzymes (such as superoxide dismutase) than other tissues. What is indisputable is that the risk of developing heart failure remains throughout a lifetime, which is of particular note in children, who have a long life-expectancy after successful treatment for cancer: 25–50% of childhood cancer survivors have signs of cardiotoxicity within 20 years of therapy, yet are generally asymptomatic.

Cardioxane®, the most widely investigated drug in the management of anthracycline-induced cardiotoxicity, acts by chelating the iron that would otherwise form the damaging anthracycline–iron complexes. The critical issue is whether Cardioxane®, or any cardioprotective drug, can decrease anthracycline-caused heart damage without increasing the risk of second malignancies, or increasing toxicity (in particular, neutropenia). These concerns have led to a reduction of use in the EU.(1)

Cardioxane® use in the EU is restricted to adults with advanced or metastatic breast cancer, who have previously received a minimum cumulative dose of 300mg/m² doxorubicin or 540mg/m² epirubicin, for which the dose ratio is 10:1 for dexrazoxane:doxorubicin (reduced from 20:1 following EU review of toxicity) and for dexrazoxane:epirubicin. France has reported four postmarketing case reports of acute myeloid leukaemia in adults with breast cancer, and there is evidence of increased myelosuppression in patients treated with dexrazoxane. There has also been reported a study that shows a decrease in tumour response rate in a study of patients with advanced breast cancer treated with doxorubicin and dexrazoxane compared with those treated with doxorubicin plus placebo. Its use in combination with adjuvant breast cancer therapy or chemotherapy is not recommended.

Cardioxane® is contraindicated in adolescents up to 18 years of age in the EU, due to evidence of serious harm in this group. This position is based on two randomised open studies that have reported a three-fold increase in the incidence of second primary malignancies in dexrazoxane-treated children compared with controls.

Concerns that the EMA position may not be fully warranted arise in part from the 2011 Cochrane Collaboration review of ten studies enrolling 1600 patients, which provided evidence that dexrazoxane prevented heart damage without interfering with the anti-tumour effects of anthracycline treatment. It was reported to have no effect on survival, that there was no significant difference in occurrence of second malignancies and that patients receiving Cardioxane® with anthracycline treatment had about one-third the risk of heart failure of patients who received anthracycline without Cardioxane®. Furthermore, the authors concluded that the use of Cardioxane®could be justified with an individualised assessment of toxicity versus benefit.(2) On that basis, the reduced use of Cardioxane® may be seen to be not objective and that it might better be left to the clinician to decide if the use of Cardioxane® is oncologically required.

Cardioxane® is one of a number of management strategies available to clinicians for anthracycline-induced cardiotoxicity, the others being:

Use of liposomal formulations, sometimes driven by gastrointestinal tract issues, has been seen to result in a lower risk of cardiotoxicity, but there is contradictory evidence to this. However, its use is restricted by the limited number of cycles in the metastatic setting (three). Cardioxane® is not licensed in the adjuvant setting. The cost of liposomal formulation is prohibitive in many countries, making its use limited to ovarian cancer. Regarding the use of liposomal anthracyclines in children, there is concern surrounding dose equivalence, in terms of both toxicity and efficacy. This is of less concern with AML, which requires two cycles of anthracycline. In general, there are insufficient data on liposomal anthracyclines, with its benefits in breast cancer minimal.

There is general consensus on the adjuvant use of anthracyclines in the treatment of breast cancer – three or four cycles of an anthracycline-containing regimen followed by three or four cycles of taxane, although some local variations (for example, weekly taxane) exist. For lower-risk patients, use of docetaxel plus cyclophosphamide or taxane alone is considered, or six cycles of an anthracycline-containing regimen.

Epirubicin cardiotoxicity concerns increase once cumulative exposure of 400mg/m², or 600mg/m² for non-high-risk patients, has been exceeded. It is rare to see clinically relevant cardiac toxicity/failure below these levels, and it tends to recur later, with the impact of the addition of trastuzumab or bevacizumab unclear, and cardiotoxicity may be being underestimated, with rate of fatigue 15–20 years post-treatment related to both cardiotoxicity and dose of anthracycline. Cardiac event rates are flat for up to eight years but, beyond 12 years, there is more doubt.

Cardiotoxocity following even the first milligram of exposure is accepted. The clinical impact of this is often viewed pragmatically, with a lack of clarity on long-term cardiac outcome, survival from cancer and, indeed, the risk-benefit issues concerning the use of Cardioxane®.

Filling the gap in data on the use of Cardioxane® in patients with breast cancer remains a priority, as this group of patients continues to achieve longer survival rates and cumulatively more treatment.

Monitoring of cardiotoxicity in paediatric oncology is determined by dose exposure and protocol. In general, an ECHO or similar test is performed prior to treatment, at intervals defined by exposure levels during treatment and on completion of treatment. Follow-up assessment is made, in general, every five years, with the percentage change as or more important than an absolute value. If MRI monitoring should indicate small echographic changes, more frequent, (annual) monitoring occurs. Long-term follow-up data exist in the UK, but not in all EU countries.

So why does Cardioxane® use continue in the US (off-label), while contraindicated in the EU, despite the fact that anthracyclines have a 50% cardiotoxicity rate? It is not unreasonable that data from continued use from outside the EU, including the recommendations from the US Children’s Oncology Group, should be acceptable for consideration by the EMA (with some caveats, for example, obesity, ethnicity and its impact on cardiotoxicity). But in addition to these data, the following could be added to make the case:

The process of formulary inclusion varies between European countries. For example, in Italy, once EMA approval has been granted, there is a national approval process, which takes around one year to complete, followed by a hospital decision, the regional process having been recently abolished. In Spain, there is an additional regional process, and individual hospitals can apply limits to its use. Additionally, at a local level, there is a special process for unlabelled use. In Germany, once EMA approval is granted, there is a national evaluation, followed by inclusion in individual hospital guidelines. In the UK, where paediatric use approval is the same as for adults, there were different approval processes in each country.

In general, formulary groups need to have identified patient groups and additional data on efficacy and toxicity.

Anthracycline will continue to be used in a variety of malignancies, and the cardiotoxicity that it causes must be prevented wherever possible, as survival improves in many cancers. As such, the future of Cardioxane® should be assured. Alternative strategies are not ideal, and their impact on treatment outcomes remains unclear. This article has highlighted what might be done to secure EU authorisation in paediatric populations, and to increase use in breast cancer patients.