Electrosclerotherapy for capillary malformations: study protocol for a randomised within-patient controlled pilot trial

Sophie E R Horbach, Albert Wolkerstorfer, Daniel Martijn de Bruin, Sanne M Jansen, Chantal M A M van der Horst, Sophie E R Horbach, Albert Wolkerstorfer, Daniel Martijn de Bruin, Sanne M Jansen, Chantal M A M van der Horst

Abstract

Introduction: The current state-of-the-art treatment modality for hypertrophic capillary malformations (CMs), laser therapy, has a considerable rate of non-responders and recurrence. Intralesional bleomycin injections (or 'sclerotherapy') are commonly used to treat venous and lymphatic malformations with an excellent effect, but these intravascular injections are not possible in CMs due to the small diameter of the vessels. Electroporation-an electric field applied to the tissue-could increase the permeability of endothelial cells, which could theoretically facilitate targeted localised bleomycin delivery. We therefore hypothesise that bleomycin injections in combination with electroporation-'electrosclerotherapy' (EST), also known as 'electrochemotherapy'-could potentially be a novel alternative treatment option for CMs.

Methods and analysis: In this randomised within-patient controlled pilot trial, 20 patients with hypertrophic CMs will be enrolled. Three regions of interest (ROIs) within the CM will be randomly allocated for treatment with (A) EST, (B) bleomycin sclerotherapy without electroporation and (C) no treatment. Patients and outcome assessors are blinded for the treatment allocation. Treatment outcome for each ROI will be measured approximately 7 weeks after the treatment procedure, using patient-reported and physician-reported global assessment scores, colorimetry, laser speckle imaging and reporting of adverse events.

Ethics and dissemination: The study protocol is approved by the ethics review committee of the Academic Medical Center, Amsterdam. Results will be published in peer-reviewed medical journals and will be presented at international conferences and scientific meetings. Study results will be fed back to the patient population through website and social media notifications.

Trial registration number: NCT02883023;Pre-results. NTR6169.

Keywords: bleomycin; capillary malformations; electrochemotherapy; electroporation; electrosclerotherapy; vascular malformations.

Conflict of interest statement

Competing interests: None declared.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Figures

Figure 1
Figure 1
Study flow chart including randomisation procedure. ROI, region of interest.
Figure 2
Figure 2
Example of the selection and numbering of three homogeneous regions of interest (ROIs) in the capillary malformation (image source: https://www.enzyklopaedie-dermatologie.de/gefaessmedizin/naevus-flammeus-ubersicht-2634#&gid=1&pid=14).
Figure 3
Figure 3
(A) Plate electrodes. (B) Hexagonal needle electrodes.

References

    1. Jacobs AH, Walton RG. The incidence of birthmarks in the neonate. Pediatrics 1976;58:218–22.
    1. Chen JK, Ghasri P, Aguilar G, et al. . An overview of clinical and experimental treatment modalities for port wine stains. J Am Acad Dermatol 2012;67:289–304. 10.1016/j.jaad.2011.11.938
    1. Kanada KN, Merin MR, Munden A, et al. . A prospective study of cutaneous findings in newborns in the United States: correlation with race, ethnicity, and gestational status using updated classification and nomenclature. J Pediatr 2012;161:240–5. 10.1016/j.jpeds.2012.02.052
    1. Wassef M, Blei F, Adams D, et al. . Vascular anomalies classification: recommendations from the international society for the study of vascular anomalies. Pediatrics 2015;136:e203–e214. 10.1542/peds.2014-3673
    1. Barsky SH, Rosen S, Geer DE, et al. . The nature and evolution of port wine stains: a computer-assisted study. J Invest Dermatol 1980;74:154–7. 10.1111/1523-1747.ep12535052
    1. Lee JW, Chung HY, Cerrati EW, et al. . The Natural history of soft tissue hypertrophy, bony hypertrophy, and nodule formation in patients with untreated head and neck capillary malformations. Dermatol Surg 2015;41:1241–5. 10.1097/DSS.0000000000000525
    1. Smoller BR, Rosen S. Port-wine stains. A disease of altered neural modulation of blood vessels? Arch Dermatol 1986;122:177–9.
    1. Revencu N, Boon LM, Mendola A, et al. . RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation. Hum Mutat 2013;34:1632–41. 10.1002/humu.22431
    1. Tan W, Nadora DM, Gao L, et al. . The somatic GNAQ mutation (R183Q) is primarily located within the blood vessels of port wine stains. J Am Acad Dermatol 2016;74:380–3. 10.1016/j.jaad.2015.09.063
    1. Frigerio A, Wright K, Wooderchak-Donahue W, et al. . Genetic Variants Associated with Port-Wine Stains. PLoS One 2015;10:e0133158 10.1371/journal.pone.0133158
    1. Nozaki T, Nosaka S, Miyazaki O, et al. . Syndromes associated with vascular tumors and malformations: a pictorial review. Radiographics 2013;33:175–95. 10.1148/rg.331125052
    1. Lanigan SW, Cotterill JA. Psychological disabilities amongst patients with port wine stains. Br J Dermatol 1989;121:209–15. 10.1111/j.1365-2133.1989.tb01800.x
    1. Masnari O, Schiestl C, Rössler J, et al. . Stigmatization predicts psychological adjustment and quality of life in children and adolescents with a facial difference. J Pediatr Psychol 2013;38:162–72. 10.1093/jpepsy/jss106
    1. Kelly KM, Choi B, McFarlane S, et al. . Description and analysis of treatments for port-wine stain birthmarks. Arch Facial Plast Surg 2005;7:287–94. 10.1001/archfaci.7.5.287
    1. Koster PH, Bossuyt PM, van der Horst CM, et al. . Assessment of clinical outcome after flashlamp pumped pulsed dye laser treatment of portwine stains: a comprehensive questionnaire. Plast Reconstr Surg 1998;102:42–8. 10.1097/00006534-199807000-00007
    1. Huikeshoven M, Koster PH, de Borgie CA, et al. . Redarkening of port-wine stains 10 years after pulsed-dye-laser treatment. N Engl J Med 2007;356:1235–40. 10.1056/NEJMoa064329
    1. Prather HB, Arndt KA. The Development of hypertrophy in port-wine stains, a common phenomenon that affects treatment recommendations. Dermatol Surg 2015;41:1246–8. 10.1097/DSS.0000000000000524
    1. Passeron T, Salhi A, Mazer JM, et al. . Prognosis and response to laser treatment of early-onset hypertrophic port-wine stains (PWS). J Am Acad Dermatol 2016;75:64–8. 10.1016/j.jaad.2016.02.1167
    1. van Drooge AM, Bosveld B, van der Veen JP, et al. . Long-pulsed 1064 nm Nd:YAG laser improves hypertrophic port-wine stains. J Eur Acad Dermatol Venereol 2013;27:1381–6. 10.1111/jdv.12021
    1. Tierney EP, Hanke CW. Alexandrite laser for the treatment of port wine stains refractory to pulsed dye laser. Dermatol Surg 2011;37:1268–78. 10.1111/j.1524-4725.2011.02079.x
    1. Horbach SE, Lokhorst MM, Saeed P, et al. . Sclerotherapy for low-flow vascular malformations of the head and neck: A systematic review of sclerosing agents. J Plast Reconstr Aesthet Surg 2016;69:295–304. 10.1016/j.bjps.2015.10.045
    1. Horbach SE, Rigter IM, Smitt JH, et al. . Intralesional bleomycin injections for vascular malformations: a systematic review and meta-analysis. Plast Reconstr Surg 2016;137:244–56. 10.1097/PRS.0000000000001924
    1. Muir T, Kirsten M, Fourie P, et al. . Intralesional bleomycin injection (IBI) treatment for haemangiomas and congenital vascular malformations. Pediatr Surg Int 2004;19:766–73. 10.1007/s00383-003-1058-6
    1. Sato D, Kurita M, Ozaki M, et al. . Extravascular injection of sclerotic agents does not affect vessels in the rat: experimental implications for percutaneous sclerotherapy of arteriovenous malformations. Eur J Vasc Endovasc Surg 2012;44:73–6. 10.1016/j.ejvs.2012.04.001
    1. Giardino R, Fini M, Bonazzi V, et al. . Electrochemotherapy a novel approach to the treatment of metastatic nodules on the skin and subcutaneous tissues. Biomed Pharmacother 2006;60:458–62. 10.1016/j.biopha.2006.07.016
    1. Di Monta G, Caracò C, Benedetto L, et al. . Electrochemotherapy as "new standard of care" treatment for cutaneous Kaposi’s sarcoma. Eur J Surg Oncol 2014;40:61–6. 10.1016/j.ejso.2013.09.002
    1. Guida M, Campana LG, Curatolo P, et al. . Local treatment with electrochemotherapy of superficial angiosarcomas: Efficacy and safety results from a multi-institutional retrospective study. J Surg Oncol 2016;114:246–53. 10.1002/jso.24287
    1. Manca G, Pandolfi P, Gregorelli C, et al. . Treatment of keloids and hypertrophic scars with bleomycin and electroporation. Plast Reconstr Surg 2013;132:621e–30. 10.1097/PRS.0b013e3182a053c8
    1. van Drooge AM, Beek JF, van der Veen JP, et al. . Hypertrophy in port-wine stains: prevalence and patient characteristics in a large patient cohort. J Am Acad Dermatol 2012;67:1214–9. 10.1016/j.jaad.2012.05.027
    1. Mir LM, Gehl J, Sersa G, et al. . Standard operating procedures of the electrochemotherapy: Instructions for the use of bleomycin or cisplatin administered either systemically or locally and electric pulses delivered by the CliniporatorTM by means of invasive or non-invasive electrodes. European Journal of Cancer Supplements 2006;4:14–25. 10.1016/j.ejcsup.2006.08.003
    1. Stefanou A, Siderov J. Society of Hospital Pharmacists of Australia Committee of Specialty Practice in Oncology. Medical errors. Dosage nomenclature of bleomycin needs to be standardised to avoid errors. BMJ 2001;322:1423–4.
    1. Stefanou A. Not again. BMJ 2001;322:548.
    1. van der Wal MB, Tuinebreijer WE, Lundgren-Nilsson Å, et al. . Differential item functioning in the Observer Scale of the POSAS for different scar types. Qual Life Res 2014;23:2037–45. 10.1007/s11136-014-0637-4
    1. Markelc B, Sersa G, Cemazar M. Differential mechanisms associated with vascular disrupting action of electrochemotherapy: intravital microscopy on the level of single normal and tumor blood vessels. PLoS One 2013;8:e59557 10.1371/journal.pone.0059557
    1. Cemazar M, Parkins CS, Holder AL, et al. . Electroporation of human microvascular endothelial cells: evidence for an anti-vascular mechanism of electrochemotherapy. Br J Cancer 2001;84:565–70. 10.1054/bjoc.2000.1625
    1. Sersa G, Cemazar M, Miklavcic D, et al. . Tumor blood flow modifying effect of electrochemotherapy with bleomycin. Anticancer Res 1999;19:4017–22.
    1. Sersa G, Jarm T, Kotnik T, et al. . Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma. Br J Cancer 2008;98:388–98. 10.1038/sj.bjc.6604168
    1. Mali B, Jarm T, Snoj M, et al. . Antitumor effectiveness of electrochemotherapy: a systematic review and meta-analysis. Eur J Surg Oncol 2013;39:4–16. 10.1016/j.ejso.2012.08.016
    1. Solari N, Spagnolo F, Ponte E, et al. . Electrochemotherapy for the management of cutaneous and subcutaneous metastasis: a series of 39 patients treated with palliative intent. J Surg Oncol 2014;109:270–4. 10.1002/jso.23481
    1. Testori A, Tosti G, Martinoli C, et al. . Electrochemotherapy for cutaneous and subcutaneous tumor lesions: a novel therapeutic approach. Dermatol Ther 2010;23:651–61. 10.1111/j.1529-8019.2010.01370.x

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren