Comment on: management of chemotherapy extravasation: ESMO–EONS clinical practice guidelines

Abstract

Recently, the ESMO–EONS clinical practice guidelines on the management of chemotherapy extravasation was published [1.Perez Fidalgo J.A. García Fabregat L. Cervantes A. et al.Management of chemotherapy extravasation: ESMO–EONS Clinical Practice Guidelines.Ann Oncol. 2012; 23: vii167-vii173Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar]. Several considerations must be discussed about this issue. The literature addressing extravasation management is limited to animal studies, case reports and small human studies. Classic randomised studies in humans for the treatment of extravasations are unthinkable because of ethical reasons. Studies in animals are generally carried out in murine models. Because of the potential problems of drug testing in rat skin, which has a thin layer of subdermal muscle (panniculus carnosus), the best model of human skin for intradermal drug testing is the use of white swine [2.Hajarizadeh H. Lebredo L. Barrie R. et al.Protective effect of doxorubicin in vitamin C or dimethyl sulfoxide against skin ulceration in the pig.Ann Surg Oncol. 1994; 1: 411-414Crossref PubMed Scopus (20) Google Scholar]. However, studies on such model are scarce. On the whole, the highest possible grade of recommendation of each measure for extravasations would be low. Extravasations, especially those caused by vesicant agents such as anthracyclines, can be devastating if untreated, resulting in a very high risk of the formation of ulcers and tissue necrosis, even loss of limb function [3.Upton J. Mulliken J.B. Murray J.E. Major intravenous extravasation injuries.Am J Surg. 1979; 137: 497-506Abstract Full Text PDF PubMed Scopus (130) Google Scholar]. A control group with placebo is unconceivable and, as defined by Pérez-Fidalgo et al., ‘a comparative study with a control group receiving the standard local care would allow clinicians to clearly define the efficacy of an antidote’ [1.Perez Fidalgo J.A. García Fabregat L. Cervantes A. et al.Management of chemotherapy extravasation: ESMO–EONS Clinical Practice Guidelines.Ann Oncol. 2012; 23: vii167-vii173Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar]. The majority of human data on anthracycline extravasations treatment include the use of dimethyl sulfoxide (DMSO) 99% combined with cooling or dexrazoxane [4.Reeves D. Management of anthracycline extravasation injuries.Ann Pharmacother. 2007; 41: 1238-1242Crossref PubMed Scopus (25) Google Scholar]. These agents were included as treatment options in extravasations occurred during anthracycline treatment with the same grade of recommendation (IIIB) [1.Perez Fidalgo J.A. García Fabregat L. Cervantes A. et al.Management of chemotherapy extravasation: ESMO–EONS Clinical Practice Guidelines.Ann Oncol. 2012; 23: vii167-vii173Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar]. Surprisingly, Table 5 lowered the level of recommendation of topical DMSO treatment to IV-B, without referencing in the main text or further explanation. We understand that both agents must have the same grade of recommendation due to similar efficacy rates and experience described in the literature [1.Perez Fidalgo J.A. García Fabregat L. Cervantes A. et al.Management of chemotherapy extravasation: ESMO–EONS Clinical Practice Guidelines.Ann Oncol. 2012; 23: vii167-vii173Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 4.Reeves D. Management of anthracycline extravasation injuries.Ann Pharmacother. 2007; 41: 1238-1242Crossref PubMed Scopus (25) Google Scholar]. A strong debate is open to determine which specific situations are suitable to use one agent or the other. The most obvious situation may be the use of dexrazoxane as a systemic antidote if an anthracycline extravasation from a central venous access occurred. Dexrazoxane is the only licensed drug for the treatment of anthracycline extravasation. However, a number of questions arise regarding the use of this antidote; the most important one is the lack of a comparative study against DMSO 99% (control arm, standard local care). Moreover, a major concern is the systemic adverse events of dexrazoxane and the financial burden to maintaining dexrazoxane in a hospital's inventory, which is of upmost importance nowadays. Finally, the authors of the guidelines also noted that ‘some countries have only DMSO at a concentration of 50%’ [1.Perez Fidalgo J.A. García Fabregat L. Cervantes A. et al.Management of chemotherapy extravasation: ESMO–EONS Clinical Practice Guidelines.Ann Oncol. 2012; 23: vii167-vii173Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar]. Concentrated DMSO 99% seems to have a superior efficacy to the diluted solution (50%), and is the only dilution recommended for the anthracycline-extravasation treatment [5.de Lemos M.L. Role of dimethylsulfoxide for management of chemotherapy extravasation.J Oncol Pharm Practice. 2004; 10: 197-200Crossref Scopus (4) Google Scholar]. This point is important to be clarified in order not to mislead the readers. As mentioned above, further research is warranted to provide more evidence for unquestionable use of these agents worldwide, mainly because DMSO is also available, with similar efficacy rates (the same grade of recommendation), more experience and is also very economical. We think that this statement could be a matter of deeper discussion. The authors have declared no conflicts of interest.