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Published on 6 October 2008

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Managing anthracycline extravasations: risk reduction and treatment with dexrazoxane

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Extravasation is the most serious side-effect associated with the use of anthracycline-based cancer therapies. Antidotal treatment with dexrazoxane will prevent serious damage, but it is important that procedures are in place to avoid treatment delays

Joris WF Uges
PharmD

Hospital Pharmacist/Pharmacologist

Central Hospital Pharmacy
the Hague/
Haga Teaching Hospital
Department of Clinical Pharmacy
The Hague
The Netherlands

During the last decade many new agents have been introduced in antitumour therapies. Monoclonal antibodies and other targeted drugs have seriously improved treatment options and survival rates for patients. However, cytotoxic agents are still the cornerstone of chemotherapeutic regimens in oncology. In the case of metastatic breast cancer, anthracycline-based therapies are still one of the most effective treatments available. Unfortunately, chemotherapy with vesicants can be hampered by serious complications, such as extravasations. The risk of extravasation in chemotherapy should not be underestimated. Incidence, according to the literature, is somewhere between 0.01% and 6%.[1]

Many important questions on managing extravasations can be answered by reading the new European Oncology Nursing Society extravasation guidelines 2007.[2] This document focuses on the role of the oncology nurse, one of the key players in this process. However, many other professionals are also involved in the process of chemotherapy. In this article I will focus on the role that the hospital pharmacist and/or medication safety officers can play.

Medication safety issues
In the last decade medication safety has become a major issue in most Dutch hospitals. HFMEA (Healthcare Failure Mode and Effects Analysis) and other risk-analysing tools are used to look for potential risks in the hospital.[3] Every hospital should have a safety management system operating by 2008. Government
policy has aimed at hospitals switching their scope towards  health and safety issues. It will no longer be acceptable for medication errors to occur on a large scale, especially not those that can be prevented easily. So, a reactive approach is no longer enough; rather, a proactive approach to medication errors is needed.

One of the fields in which medication errors have led to serious complications is oncology. Even now there are reports of deaths by medication errors with cytotoxic agents. And on closer examination, looking at the worst complications and biggest patient risks with medications in oncology, chemotherapy with anthracyclines ranks high. One of the reasons for the high risks associated with anthracycline therapy is the serious complications that occur due to extravasations. These critical events can lead to severe tissue damage, necrosis and serious morbidity.

On the other hand, the good news is that antidotal therapy is now available that can seriously minimise damage. So, as well as making efforts to prevent the incident of extravasation taking place, efforts also need to be made to prevent damage if extravasation does occur. This two-way approach fits a hazard
analysis following the “bow-tie model”, a risk analysis tool adapted from methods developed in the petrochemical and aviation industries.[4,5] Prospectively, the risk factors that might lead to a critical event such as extravasation and its consequences need to be sorted out systematically. After getting these clear, barriers to neutralise the risks and recovery measures to minimise damage after an incident need to be made. I shall discuss some examples of both. However, since we
are dealing with a medication process, which is largely dependent on your own situation, I advocate that the medication safety officer or hospital pharmacist perform a risk analysis. This topic can be an excellent start to a focus on reducing complications from medication errors in your hospital.

Prevention of extravasation
In 2004 experienced a serious extravasation episode with an anthracycline because of a misplaced central venous catheter (CVC ).[6] When we analysed this case we discovered that the main reason for this incident was incomplete following of procedures. The misplacement of the CVC was missed because of one-way X-ray positioning, and blood withdrawal was omitted
before administration of the chemotherapy. Unfortunately, we had not carried out a risk analysis before this incident, and a proactive approach might have prevented this case from happening.

After this incident we changed our procedures and trained personnel. Since then, no extravasation of a vesicant by a CVC has taken place in our hospital. Therefore education and using the right procedures might be very effective in reducing the risks of extravasation.

As well as training staff, educating patients and optimising protocols, other actions can also be taken to reduce the risks of extravasation. Vein selection, equipment selection and the infusion procedure are of importance and also need special attention.[2]

Extravasation and antidotal therapy
One of the most important facts about preventing extravasations is that no matter what you do to prevent them they will still occur. Thin, fragile and mobile veins are often seen in patients with cancer, resulting in a higher risk of extravasation. As discussed, it is important that everyone involved is familiar with the increase risk of extravasation. Patients need to be thoroughly informed, and nursing staff should be trained to recognise the symptoms. Although the hospital pharmacist can also play a role in education, the responsibility for this mostly falls to the oncologist and nursing staff. If an extravasation with anthracyclines is established then the hospital pharmacist comes into play.

In Europe, dexrazoxane has an orphan drug registration as antidotal therapy in anthracycline extravasations. In earlier issues of this journal other specialists have pointed out its efficacy, based on two multicentre trials.[7] Although these studies are single-arm and not controlled, the results compared with a historical control are very promising. More information about dexrazoxane is given in Table 1.

I want to discuss some other features or “recovery measures” that may play an important factor in success of the antidotal therapy. First, the first dose of dexrazoxane needs to be given within six hours of extravasation. This timeframe is based on experimental data gathered in mice.[8] However, if you take a closer look at the data it is clear that the six-hour interval is
the maximum time interval. The sooner dexrazoxane is given, the greater its effect.

Early recognition of the extravasation and physician knowledge of the antidotal therapy comprise the first step. Availability of dexrazoxane is the second. In my opinion, rather than the six-hour timeframe, “as soon as possible” should be the starting point for treatment. This is why in our facility we decided to have dexrazoxane in stock in our hospital pharmacy. Another method would be to make arrangements with neighbouring
hospitals or other regional suppliers.

[[HPE40.53]]

In 2004 we were not familiar with dexrazoxane, and its availability was poor. We had to import the drug from France, and serious time delays of approximately 24 hours could not be avoided. So, if no prior arrangements have been made, the six-hour timeframe is rather short, and the chances of an optimal outcome decrease rapidly.

Preparation facilities are another concern of the hospital pharmacist. Dexrazoxane is itself a cytotoxic agent and needs to be prepared under controlled conditions. Compounding facilities for chemotherapy preparation in the hospital pharmacy are probably best suited. To minimise time delay, pharmacy personnel should be instructed and protocols should be available.

[[HPE40.54]]

Conclusion
Good procedures, early recognition and availability of dexrazoxane are almost as important as the antidotal therapy itself. Chemotherapy with anthracyclines ranks high in harmful medication therapies. A prospective risk analysis might be useful in reducing the risks of an anthracycline extravasation.

The hospital pharmacist or medication safety officer can play an important role in performing the risk analysis and converting the results into risk-reducing actions. Nursing personnel and physicians can play an important role in reducing the incidence of extravasations occurring. However, extravasations cannot be eliminated completely, so the hospital pharmacist needs to be
prepared as well.

Antidotal therapy with dexrazoxane needs to be available for administration within six hours of extravasation, but preferably sooner.

References
1. Schulmeister L. Managing vesicant extravasations. The Oncologist 2008;13:284-8.
2. EONS. Extravasation guidelines 2007. Guidelines implementation toolkit [cited 2008 August 25]. Available from: http://www.cancerworld.org/CancerWorld/getStaticModFile.aspx?id=2340
3. Spath P. Using Failure Mode and Effects Analysis to improve patient safety. Brown-Spath and Associates, Forest Grove, Ore, USA. Ahorn J 2003;78(1):16-37; quiz 41-4.
4. Hudson PTW. Applying the lessons of high risk industries to health care. Qual Saf Health Care 2003;12 Suppl 1:i7-21.
5. Zuijderduijn C. Risk management by Shell Refinery/ Chemicals at Pernis, the Netherlands 1999. Shell BV, Rotterdam, the Netherlands, 1999 [cited 2008 August 25]. Available from: http://mahbsrv.jrc.it/proceedings/
greece-nov-1999/b4-zuijderduijn-shell-z.pdf
6. Uges JWF, Vollaard AM, Wilms EB, Brouwer RE. Intrapleural extravastion of epirubicin, 5-fluouracil, and cyclophosphamide treated with dexrazoxane. Int J Clin Oncol 2006;11:467-70.
7. Mouridsen HT, Langer SW, Buter J, Eidtmann H, Rosti G, de Wit M, Knoblauch P, Rasmussen A, Dahlstrom K, Jensen PB, Giaccone G. Treatment of anthracycline extravasation with Savene (dexrazoxane): results from two prospective clinical
multicentre studies. Ann Oncol 2007;18:546-50.
8. Langer SW, Shested M, Jensen PB. Treatment of
anthracycline extravasation with dexrazoxane.
Clin Cancer Res 2000;6:3680-6.



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