Reply to ‘Comment on: management of chemotherapy extravasation: ESMO–EONS clinical practice guidelines'
Authors: J.A. Pérez-Fidalgo, A. Cervantes
Journal: Annals of Oncology (2013)

We have read with interest the letter by Conde-Estévez and Mateu-de-Antonio [1.Conde-Estévez D, Mateu-de-Antonio J Comment on: management of chemotherapy extravasation: ESMO–EONS clinical practice guidelines. Ann Oncol. 2013; 24: 1128-1129Google Scholar] in which they affirm that both DMSO 99% and dexrazoxane should be considered as antidotes against extravasation due to anthracyclines with a similar level of evidence. Evidence on the use of DMSO in anthracycline extravasation is mainly supported by two prospective non-randomized, single-arm studies. In 1988, a case–control pilot study included only 16 fully assessable patients [2.Olver I.N. Aisner J. Hament A. et al.A prospective study of topical dimethyl sulfoxide for treating anthracycline extravasation.J Clin Oncol. 1988; 6: 1732-1735Crossref PubMed Scopus (100) Google Scholar]. None of the patients treated with DMSO 99% presented an ulcer on the extravasation area. Later in 1995, another prospective single-arm study [3.Bertelli G. Gozza A. Forno G.B. et al.Topical dimethylsulfoxide for the prevention of soft tissue injury after extravasation of vesicant cytotoxic drugs: a prospective clinical study.J Clin Oncol. 1995; 13: 2851-2855Crossref PubMed Scopus (153) Google Scholar] described that only 1 patient out of 65 developed skin ulceration after anthracycline extravasation treated with DMSO. Toxicity was mild, only 5.5% of patients complained with mild local burning after topical DMSO application and 27.5% reported an unpleasant breath odor. Although in the ESMO–EONS guidelines for chemotherapy extravasation, it is mentioned that some countries only have the presentation of DMSO 50% [4.Pérez-Fidalgo J.A. García-Fabregat L. Cervantes A. et al.ESMO Guidelines Working Group.Ann Oncol. 2012; 23: vii167-vii173doi:10.1093/annonc/mds294PubMed Google Scholar], it should be clarified that, as mentioned by Conde-Estevez and Mateu-de-Antonio, the available evidence is only for DMSO 99%. The use of dexrazoxane as an antidote for anthracycline extravasation is mainly based on two muticentre studies, the TT01 and TT02 published as a pooled analysis by Mouridsen et al. in 2007 [5.Mouridsen H.T. Langer S.W. Buter J. et al.Treatment of anthracycline extravasation with Savene (dexrazoxane): results from two prospective clinical multicentre studies.Ann Oncol. 2007; 18: 546-550doi:10.1093/annonc/mdl413Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar]. These studies included 57 assessable patients. Hematologic and hepatic toxicity secondary to dexrazoxane was frequent. Only one patient (1.7%) presented a surgery-requiring necrosis. These results led the authorities to approve the use of dexrazoxane (Savene®) in this setting. Although both the compounds are supported by single-arm prospective studies including a similar number of patients, we consider that there are some important points that should be underlined. First, the requirement for quality standards was not the same. The trial by Mouridsen et al. was conducted in accordance with Good Clinical Practice, approved by ethical boards and the patients were asked to give written informed consent before antidote administration. These aspects are not described in the studies with DMSO. Second, the study design was different. In the dexrazoxane trial, it was required that extravasation was diagnosed by positive fluorescence microscopy in at least one skin biopsy. In the studies with DMSO, diagnosis of extravasation was based only on clinical signs and symptoms. Moreover, the studies with dexrazoxane were specifically designed for anthracycline extravasation, and included an independent evaluation of efficacy and safety data. In the case of TT02 trial, a previous calculation of the sample size was made. None of these points were included in the studies with DMSO. According to these aspects, and considering that both the treatments have not been compared, it should be stated that the trials with dexrazoxane support a slightly superior level of evidence. Based on these observations, we have considered that both the options (cooling followed with topical DMSO 99% or cooling followed with intravenous dexrazoxane) could be considered for the treatment of an anthracycline extravasation through the peripheral line but with a level of evidence III-B for dexrazoxane and IV-B for DMSO 99%. The authors have declared no conflicts of interest.