Position Statement on dexrazoxane in the Treatment of Anthracycline Extravasation

Summary:
· dexrazoxane is an important development which is licensed on the basis of a good clinical trial.
· dexrazoxane should be available either immediately or within 6 hours of a positively identified anthracycline extravasation.
· The licensed 3-day course should be administered in anthracycline extravasation injuries; to all large volume peripheral extravasation with an unequivocal diagnosis (volumes greater than 5mls), those of uncertain diagnosis, but where an anthracycline is the suspected drug, greater than 10mls in volume or extravasations from a central or peripherally inserted long line.
· Anthracycline extravasations between 1.5 and 5ml or those in whom the diagnosis may not be certain, up to volumes of 10mls, still need treating promptly, however the role of dexrazoxane is still unclear, and in these situations DMSO is the antidote of choice.
· Considering the above recommendations then if the provision of dexrazoxane is to be at a network or area level then based on the incidence of anthracycline extravasation and their translation into necrotic ulcers, one kit per 300,000 to 400,000 population would seem appropriate.
· The introduction of this new antidote needs to be audited for its efficacy in actual practice, and further research work performed to better refine and develop its use.

The recent launch of dexrazoxane (Savene TM) as a licensed product for the treatment of anthracycline extravasation is to be welcomed as a very positive step in the development of both the science and clinical management of extravasation injuries.

dexrazoxane looks to be an excellent compound, with good translation of its under lying pharmacological action into clinical application. Furthermore TopoTarget are to be congratulated for performing the first properly organised clinical trials in the field of extravasation with biopsy-proven extravasation injuries. Whilst in a highly critical academic sense; dexrazoxane verses DMSO (Dimethyl Sulphoxide) or even more radical stratification for volume extravasated and small volume incidence receiving no intervention or symptom management only would have perhaps been better studies giving more meaningful data. This however should not detract from the achievement of all the collaborators. The two trials reported in Annals of Oncology are one of the most important steps forward for extravasation since Fissons / CP / Wockhardt licensed hyaluronidase in collaboration with Lilly for the treatment of Vinca extravasations.

Therefore Chemotherapy Units should make dexrazoxane available in the light of subscribing to evidence based medicine. Also in an increasingly legitative NHS the availability of a licensed product such as this not been available in a chemotherapy unit or if unit could not demonstrate that it had timely access to it could be construed as a failure to discharge the trusts / networks ‘duty of care’.

This said I still believe there remain a number of issues / questions which will require further work or audit to answer, these are:

  • When precisely should dexrazoxane (Savene TM) be used?

At The National Extravasation Information Service, we know that the volume of drug extravasating before being diagnosed as an extravasation injury is falling.

Year 1985 (n=46) 1995 (n=74) 2005 (n=97)
Estimated Mean Volume 11.6 ml 7.2 ml 3.1 ml

This has lead me to question the value of intervention in very low volume extravasations i.e. below1.5ml, especially when we know that the intervention and or the antidote(s) may cause complications in their own right, and that the body has some natural homeostatic mechanisms to buffer injury from ‘injected’ toxins.

There are therefore clearly groups who should receive dexrazoxane as soon as is practically possible after the anthracycline extravasation, these are:

A/ Large volume extravasation were the diagnosis is certain i.e. volumes greater than 5ml,

B/ Large volume (greater then 10ml) extravasations or suspected extravasations were the involvement of an anthracycline is the most probable causative drug and

C/ Extravasation from a central or PIC line.

We are thus left with a group of extravasation with volumes between 1.5 and 10 mls where there may be a variable degree of uncertainty as to the diagnosis. Undeniably intervention is important in this group; but is a 3 day course of IV dexrazoxane at £6,750 backed by trial data and efficacy or a 14 day course of topical treatment with DMSO and cooling at a maximum of £175 but based on anecdotal and case reports, the most appropriate? We are not yet able to conclude with certainty. My own research which identifies prior to therapy patients according to their relative risk of going onto develop an extravasation injury; thus in the future it may be possible to link the believed volume of extravasated drug to the patient specific risk score, and so allow us to better define appropriate patients to receive dexrazoxane. Whilst we await this research’s validation we need to put in place local arrangements to scrutinise these ‘mid volume’ extravasations, this is likely to be a multidisciplinary team but probable lead by the chemotherapy CNS.

  • Does dexrazoxane work for Liposomal Anthracycline Preparation?

There was only a single Liposomal patient in the licensing studies, who did respond but not as well as other patients. It is impossible to draw any conclusions from this single patient, however it is believable that dexrazoxane may not be as effective in these patients, as the initially injury is ‘masked’ by the Liposomal envelope surrounding the anthracycline. These injuries develop into as serious an injury as their non Liposomal counterparts although the time course is delay by as much as 10 days. If dexrazoxane can not penetrate the liposome then it is likely to be less effective or even completely ineffective, and may therefore exclude this group of anthracycline patients.

Other Issues

· The cost of dexrazoxane (Savene TM) is not cheap at £6,750 for a three-day treatment pack; however it is quite cleverly priced so as to make it cheaper than having to settle with a patient for the distress and ‘functional’ loss that resulted from their extravasation injury. These injuries seem to always settle out of court in my experience but settle at around the £10,000 mark.
· Best model for provision of this new antidote, large centres using anthracycline in either haematology or oncology units, would most likely benefit from purchasing individual kits to hold ‘on site’, however in view of the cost of the kits or if large amounts of anthracycline are administered in satellite or peripheral units, then the cancer network may feel it more appropriate to purchase and hold centrally a number of dexrazoxane kits. If the provision of dexrazoxane is to be at a network or area level then based on the incidence of anthracycline extravasation and their translation into necrotic ulcers, one kit per 3 to 400,000 population would seem appropriate.


Future research work:

· The National Extravasation Information Service should track the use of dexrazoxane in the UK, all hospitals purchasing a treatment pack would inform The National Extravasation Information Service by e-mail , and then when they used the pack, inform The National Extravasation Information Service again by e-mail with a contact name and phone number. The National Extravasation Information Service would then contact the user to arrange a convenient time to conduct a telephone interview regarding the circumstances and decision making process which lead to the use of the dexrazoxane and the outcome of the intervention.
· Conduct an evaluation of dexrazoxane for low volume and/or low risk patient who experience an anthracycline extravasation, tackling questions around the usefulness of smaller volumes/doses and or shorter courses.
· Conduct an evaluation of the efficacy of dexrazoxane in Liposomal anthracycline.
· Evaluate the efficacy of late use dexrazoxane in established anthracycline extravasations, up to one month post incidence.
· Conduct an evaluation of the efficacy of dexrazoxane in other topoisomerase II anticancer drugs.

Useful links

bupa.co.th

Declaration

I have contributed to a TopoTarget sponsored consensus expert panel on the role and position of dexrazoxane, which is available via the Savene website, I believe this document is broadly in line with this position statement. The National Extravasation Information Service has also approached TopoTarget for an independent research grant to further develop the practical treatment preventions and education concerning extravasation.

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