Electrosclerotherapy for capillary malformations|
|- candidate number||25538|
|- NTR Number||NTR6169|
|- ISRCTN||ISRCTN no longer applicable|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||15-nov-2016|
|- Secondary IDs||2016_239 NL58824.018.16|
|- Public Title||Electrosclerotherapy for capillary malformations|
|- Scientific Title||Electrosclerotherapy as a novel treatment option for capillary malformations: a pilot study|
|- hypothesis||Capillary malformations (¡®port-wine stains¡¯) are congenital abnormalities of the capillary vessels of the skin, causing a red or purple color. Laser therapy is currently the only widely accepted treatment option, but treatment response is suboptimal in approximately half of patients. In capillary malformations with hypertrophy, increased thickness of the (sub)cutaneous tissue, treatment response is even poorer. Hence, there is a need for an alternative treatment option for capillary malformations.
Intralesional bleomycin injections (sclerotherapy) are commonly used to treat vascular malformations of larger sized vessels, but cannot be used in capillary malformations because the vessel diameter is too small for accurate intravascular injections. |
Therefore, bleomycin cannot reach the endothelial cells where it has its therapeutic sclerosing effect.
¡®Electroporation' is a physical phenomenon that increases the permeability of cell membranes through the exposure of cells to an electric field, which allows molecules and drugs to easily cross cell membranes. The combination of electroporation and the regular intralesional bleomycin injections (¡®electrosclerotherapy¡¯) could facilitate localized bleomycin delivery to endothelial cells and subsequent vascular depletion, ultimately leading to regression of the capillary malformation. Electrosclerotherapy has been safely used in many skin lesions with high effectiveness rates, especially in vascular tumors. We hypothesize that electrosclerotherapy can also be a feasible and safe alternative treatment option for capillary malformations.
|- Healt Condition(s) or Problem(s) studied||Vascular malformations, Capillary malformations|
|- Inclusion criteria||- Patients with ¡İ1 completely or partially hypertrophic capillary malformation not exclusively located in the skin of the face, the skin overlying joints or in mucosal tissue|
- Age ¡İ 18 years
- Fitzpatrick skin type 1-3 without evident sun tan
|- Exclusion criteria||- Patients with capillary malformations exclusively located in the face, in the skin overlying joints or in mucosa |
- Pregnant or breastfeeding women
- Women with childbearing potential not using contraception
- Patients with chronic renal dysfunction of GFR <50 ml/minute
- Patients with chronic pulmonary dysfuction, active pulmonary infections or previous bleomycin lung toxicity
- Patients with ataxia teleangiectasia
- Patients with previous allergic reactions to bleomycin
- Patients who already received the maximum dose of bleomycin (400 units mg or 400000 IU/m2)
- Patients with implanted electrical devices such as pacemakers or ICD's
- Patients with clinically manifested arrhythmia
- Patients with epilepsy
- Patients who are not able to return to the hospital for follow-up visits
- Patients who are likely not able to understand the terms and risks of the study (e.g. cognitive impairment)
- Legally incompetent adults
- Patients of which informed consent was not obtained
|- mec approval received||yes|
|- multicenter trial||no|
|- Type||2 or more arms, randomized|
|- planned startdate ||20-dec-2016|
|- planned closingdate||20-dec-2017|
|- Target number of participants||20|
|- Interventions||All participants undergo one intervention session in which 3 homogeneous 1.5x1.5 cm parts of the capillary malformation are randomly allocated to  electrosclerotherapy,  bleomycin injection without electroporation or  no treatment. |
|- Primary outcome||- (Change in) global assessment of color, thickness, nodularity, pliability, surface area and overall improvement by both the patient and a blinded observer using a global assessment score and the POSAS instrument. |
- In terms of safety, we will investigate the number and type(s) of adverse events.
|- Secondary outcome||- (Change in) color measured using colorimetry|
- (Change in) perfusion of the capillary malformations, measured using optical imaging techniques.
|- Timepoints||The patient visits the hospital 3 times:  treatment visit (t=0),  wound check visit (t=1 week) and  outcome measurement visit (t=7 weeks). |
|- Trial web site|
|- CONTACT FOR PUBLIC QUERIES||Prof.dr. C.M.A.M. van der Horst|
|- CONTACT for SCIENTIFIC QUERIES||Prof.dr. C.M.A.M. van der Horst|
|- Sponsor/Initiator ||Academic Medical Center (AMC), Amsterdam|
(Source(s) of Monetary or Material Support)
|Academic Medical Center (AMC)|
|- Publications||1. Jacobs AH, Walton RG. The incidence of birthmarks in the neonate. Pediatrics. 1976;58(2):218-22.|
2. Chen JK, Ghasri P, Aguilar G, van Drooge AM, Wolkerstorfer A, Kelly KM, et al. An overview of clinical and experimental treatment modalities for port wine stains. Journal of the American Academy of Dermatology. 2012;67(2):289-304.
3. Kanada KN, Merin MR, Munden A, Friedlander SF. A prospective study of cutaneous findings in newborns in the United States: correlation with race, ethnicity, and gestational status using updated classification and nomenclature. The Journal of pediatrics. 2012;161(2):240-5.
4. Barsky SH, Rosen S, Geer DE, Noe JM. The nature and evolution of port wine stains: a computer-assisted study. The Journal of investigative dermatology. 1980;74(3):154-7.
5. Lee JW, Chung HY, Cerrati EW, O TM, Waner M. The Natural History of Soft Tissue Hypertrophy, Bony Hypertrophy, and Nodule Formation in Patients With Untreated Head and Neck Capillary Malformations. Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al]. 2015;41(11):1241-5.
6. Smoller BR, Rosen S. Port-wine stains. A disease of altered neural modulation of blood vessels? Archives of dermatology. 1986;122(2):177-9.
7. Nozaki T, Nosaka S, Miyazaki O, Makidono A, Yamamoto A, Niwa T, et al. Syndromes associated with vascular tumors and malformations: a pictorial review. Radiographics : a review publication of the Radiological Society of North America, Inc. 2013;33(1):175-95.
8. Lanigan SW, Cotterill JA. Psychological disabilities amongst patients with port wine stains. The British journal of dermatology. 1989;121(2):209-15.
9. Masnari O, Schiestl C, Rossler J, Gutlein SK, Neuhaus K, Weibel L, et al. Stigmatization predicts psychological adjustment and quality of life in children and adolescents with a facial difference. J Pediatr Psychol. 2013;38(2):162-72.
10. Wassef M, Blei F, Adams D, Alomari A, Baselga E, Berenstein A, et al. Vascular Anomalies Classification: Recommendations From the International Society for the Study of Vascular Anomalies. Pediatrics. 2015;136(1):e203-e14.
11. Kelly KM, Choi B, McFarlane S, Motosue A, Jung B, Khan MH, et al. Description and analysis of treatments for port-wine stain birthmarks. Archives of facial plastic surgery. 2005;7(5):287-94.
12. Koster PH, Bossuyt PM, van der Horst CM, Gijsbers GH, van Gemert MJ. Assessment of clinical outcome after flashlamp pumped pulsed dye laser treatment of portwine stains: a comprehensive questionnaire. Plastic and reconstructive surgery. 1998;102(1):42-8.
13. Huikeshoven M, Koster PH, de Borgie CA, Beek JF, van Gemert MJ, van der Horst CM. Redarkening of port-wine stains 10 years after pulsed-dye-laser treatment. The New England journal of medicine. 2007;356(12):1235-40.
14. Prather HB, Arndt KA. The Development of Hypertrophy in Port-Wine Stains, a Common Phenomenon that Affects Treatment Recommendations. Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al]. 2015;41(11):1246-8.
15. Passeron T, Salhi A, Mazer JM, Lavogiez C, Mazereeuw-Hautier J, Galliot C, et al. Prognosis and response to laser treatment of early-onset hypertrophic port-wine stains (PWS). Journal of the American Academy of Dermatology. 2016;75(1):64-8.
16. Horbach SE, Lokhorst MM, Saeed P, de Gouyon Matignon de Pontouraude CM, Rothova A, van der Horst CM. Sclerotherapy for low-flow vascular malformations of the head and neck: A systematic review of sclerosing agents. Journal of plastic, reconstructive & aesthetic surgery : JPRAS. 2015.
17. Horbach SE, Rigter IM, Smitt JH, Reekers JA, Spuls PI, van der Horst CM. Intralesional Bleomycin Injections for Vascular Malformations: A Systematic Review and Meta-Analysis. Plastic and reconstructive surgery. 2016;137(1):244-56.
18. Muir T, Kirsten M, Fourie P, Dippenaar N, Ionescu GO. Intralesional bleomycin injection (IBI) treatment for haemangiomas and congenital vascular malformations. Pediatric surgery international. 2004;19(12):766-73.
19. Sato D, Kurita M, Ozaki M, Kaji N, Takushima A, Harii K. Extravascular injection of sclerotic agents does not affect vessels in the rat: experimental implications for percutaneous sclerotherapy of arteriovenous malformations. European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery. 2012;44(1):73-6.
20. Giardino R, Fini M, Bonazzi V, Cadossi R, Nicolini A, Carpi A. Electrochemotherapy a novel approach to the treatment of metastatic nodules on the skin and subcutaneous tissues. Biomed Pharmacother. 2006;60(8):458-62.
21. Di Monta G, Caraco C, Benedetto L, La Padula S, Marone U, Tornesello ML, et al. Electrochemotherapy as "new standard of care" treatment for cutaneous Kaposi's sarcoma. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2014;40(1):61-6.
22. 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(3):e59557.
23. Cemazar M, Parkins CS, Holder AL, Chaplin DJ, Tozer GM, Sersa G. Electroporation of human microvascular endothelial cells: evidence for an anti-vascular mechanism of electrochemotherapy. British journal of cancer. 2001;84(4):565-70.
24. Sersa G, Cemazar M, Miklavcic D, Chaplin DJ. Tumor blood flow modifying effect of electrochemotherapy with bleomycin. Anticancer research. 1999;19(5b):4017-22.
25. Sersa G, Jarm T, Kotnik T, Coer A, Podkrajsek M, Sentjurc M, et al. Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma. British journal of cancer. 2008;98(2):388-98.
26. Mali B, Jarm T, Snoj M, Sersa G, Miklavcic D. Antitumor effectiveness of electrochemotherapy: a systematic review and meta-analysis. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2013;39(1):4-16.
27. Solari N, Spagnolo F, Ponte E, Quaglia A, Lillini R, Battista M, et al. Electrochemotherapy for the management of cutaneous and subcutaneous metastasis: a series of 39 patients treated with palliative intent. Journal of surgical oncology. 2014;109(3):270-4.
28. Manca G, Pandolfi P, Gregorelli C, Cadossi M, de Terlizzi F. Treatment of keloids and hypertrophic scars with bleomycin and electroporation. Plastic and reconstructive surgery. 2013;132(4):621e-30e.
29. van Drooge AM, Beek JF, van der Veen JP, van der Horst CM, Wolkerstorfer A. Hypertrophy in port-wine stains: prevalence and patient characteristics in a large patient cohort. Journal of the American Academy of Dermatology. 2012;67(6):1214-9.
30. Yamamoto T. Bleomycin and the skin. The British journal of dermatology. 2006;155(5):869-75.
31. Zhao JH, Zhao YF, Chen XM, Zheng X, Zhang WF. Histological investigation of veins and venous malformations after injection of sclerosing agents. Asian Journal of Oral and Maxillofacial Surgery. 2002;14(4):226-31.
32. Yamamoto T. The bleomycin-induced scleroderma model: what have we learned for scleroderma pathogenesis? Archives of dermatological research. 2006;297(8):333-44.
33. Saitta P, Krishnamurthy K, Brown LH. Bleomycin in dermatology: a review of intralesional applications. Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al]. 2008;34(10):1299-313.
34. Mir LM, Gehl J, Sersa G, Collins CG, Garbay J-R, Billard V, 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 Cliniporator TM by means of invasive or non-invasive electrodes. European Journal of Cancer Supplements. 2006;4(11):14-25.
35. Bezemer R, Klijn E, Khalilzada M, Lima A, Heger M, van Bommel J, et al. Validation of near-infrared laser speckle imaging for assessing microvascular (re)perfusion. Microvasc Res. 2010;79(2):139-43.
36. Sharif SA, Taydas E, Mazhar A, Rahimian R, Kelly KM, Choi B, et al. Noninvasive clinical assessment of port-wine stain birthmarks using current and future optical imaging technology: a review. The British journal of dermatology. 2012;167(6):1215-23.
37. Qiu H, Zhou Y, Gu Y, Ang Q, Zhao S, Wang Y, et al. Monitoring microcirculation changes in port wine stains during vascular targeted photodynamic therapy by laser speckle imaging. Photochem Photobiol. 2012;88(4):978-84.
38. van der Wal MB, Tuinebreijer WE, Lundgren-Nilsson A, Middelkoop E, van Zuijlen PP. Differential item functioning in the Observer Scale of the POSAS for different scar types. Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation. 2014;23(7):2037-45.
39. Curatolo P, Quaglino P, Marenco F, Mancini M, Nardo T, Mortera C, et al. Electrochemotherapy in the treatment of Kaposi sarcoma cutaneous lesions: a two-center prospective phase II trial. Ann Surg Oncol. 2012;19(1):192-8.
40. Guida M, Campana LG, Curatolo P, Strippoli S, Bonadies A, Grilz G, et al. Local treatment with electrochemotherapy of superficial angiosarcomas: Efficacy and safety results from a multi-institutional retrospective study. Journal of surgical oncology. 2016;114(2):246-53.
41. Testori A, Tosti G, Martinoli C, Spadola G, Cataldo F, Verrecchia F, et al. Electrochemotherapy for cutaneous and subcutaneous tumor lesions: a novel therapeutic approach. Dermatol Ther. 2010;23(6):651-61.
42. Bai N, Chen YZ, Fu YJ, Wu P, Zhang WN. A clinical study of pingyangmycin sclerotherapy for venous malformation: an evaluation of 281 consecutive patients. Journal of clinical pharmacy and therapeutics. 2014;39(5):521-6.
43. Bai Y, Jia J, Huang XX, Alsharif MJ, Zhao JH, Zhao YF. Sclerotherapy of microcystic lymphatic malformations in oral and facial regions. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. 2009;67(2):251-6.
44. Chaudry G, Guevara CJ, Rialon KL, Kerr C, Mulliken JB, Greene AK, et al. Safety and Efficacy of Bleomycin Sclerotherapy for Microcystic Lymphatic Malformation. Cardiovascular and interventional radiology. 2014.
45. Chen J, Zheng G, Liao G, Fu Z, Li J, Zhang T, et al. Digital subtraction angiography-guided percutaneous sclerotherapy of venous malformations with pingyangmycin and/or absolute ethanol in the maxillofacial region. J Oral Maxillofac Surg. 2010;68(9):2258-66.
46. Erikci V, Hosgor M, Yildiz M, Ornek Y, Aksoy N, Okur O, et al. Intralesional bleomycin sclerotherapy in childhood lymphangioma. The Turkish journal of pediatrics. 2013;55(4):396-400.
47. Jia R, Xu S, Huang X, Song X, Pan H, Zhang L, et al. Pingyangmycin as first-line treatment for low-flow orbital or periorbital venous malformations: evaluation of 33 consecutive patients. JAMA ophthalmology. 2014;132(8):942-8.
48. Karavelioglu A, Temucin CM, Tanyel FC, Ciftci AO, Senocak ME, Karnak I. Sclerotherapy with bleomycin does not adversely affect facial nerve function in children with cervicofacial cystic lymphatic malformation. Journal of pediatric surgery. 2010;45(8):1627-32.
49. Kim KH, Sung MW, Roh JL, Han MH. Sclerotherapy for congenital lesions in the head and neck. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery. 2004;131(3):307-16.
50. Kumar V, Kumar P, Pandey A, Gupta DK, Shukla RC, Sharma SP, et al. Intralesional bleomycin in lymphangioma: an effective and safe non-operative modality of treatment. Journal of cutaneous and aesthetic surgery. 2012;5(2):133-6.
51. Mathur NN, Rana I, Bothra R, Dhawan R, Kathuria G, Pradhan T. Bleomycin sclerotherapy in congenital lymphatic and vascular malformations of head and neck. International journal of pediatric otorhinolaryngology. 2005;69(1):75-80.
52. Mohan AT, Adams S, Adams K, Hudson DA. Intralesional bleomycin injection in management of low flow vascular malformations in children. Journal of plastic surgery and hand surgery. 2014:1-5.
53. Niramis R, Watanatittan S, Rattanasuwan T. Treatment of cystic hygroma by intralesional bleomycin injection: experience in 70 patients. European journal of pediatric surgery : official journal of Austrian Association of Pediatric Surgery [et al] = Zeitschrift fur Kinderchirurgie. 2010;20(3):178-82.
54. Orford J, Barker A, Thonell S, King P, Murphy J. Bleomycin therapy for cystic hygroma. Journal of pediatric surgery. 1995;30(9):1282-7.
55. Paramasivam S, Fay A, Fifi J, Berenstein A. O-015 image guided bleomycin sclerotherapy for orbital lymphatic malformation. Journal of neurointerventional surgery. 2014;6 Suppl 1:A8-9.
56. Rawat JD, Sinha SK, Kanojia RP, Wakhlu A, Kureel SN, Tandon RK. Non surgical management of cystic lymphangioma. Indian journal of otolaryngology and head and neck surgery : official publication of the Association of Otolaryngologists of India. 2006;58(4):355-7.
57. Rozman Z, Thambidorai RR, Zaleha AM, Zakaria Z, Zulfiqar MA. Lymphangioma: Is intralesional bleomycin sclerotherapy effective? Biomedical imaging and intervention journal. 2011;7(3):e18.
58. Sainsbury DC, Kessell G, Fall AJ, Hampton FJ, Guhan A, Muir T. Intralesional bleomycin injection treatment for vascular birthmarks: a 5-year experience at a single United Kingdom unit. Plastic and reconstructive surgery. 2011;127(5):2031-44.
59. Sandlas G, Kothari P, Karkera P, Gupta A. Bleomycin: A worthy alternative. Indian journal of plastic surgery : official publication of the Association of Plastic Surgeons of India. 2011;44(1):50-3.
60. Spence J, Krings T, TerBrugge KG, Agid R. Percutaneous treatment of facial venous malformations: a matched comparison of alcohol and bleomycin sclerotherapy. Head & neck. 2011;33(1):125-30.
61. Spence J, Krings T, terBrugge KG, da Costa LB, Agid R. Percutaneous sclerotherapy for facial venous malformations: subjective clinical and objective MR imaging follow-up results. AJNR American journal of neuroradiology. 2010;31(5):955-60.
62. Sung MW, Chang SO, Choi JH, Kim JY. Bleomycin sclerotherapy in patients with congenital lymphatic malformation in the head and neck. American journal of otolaryngology. 1995;16(4):236-41.
63. Yue H, Qian J, Elner VM, Guo J, Yuan YF, Zhang R, et al. Treatment of orbital vascular malformations with intralesional injection of pingyangmycin. The British journal of ophthalmology. 2013;97(6):739-45.
64. Zhang J, Li HB, Zhou SY, Chen KS, Niu CQ, Tan XY, et al. Comparison between absolute ethanol and bleomycin for the treatment of venous malformation in children. Experimental and therapeutic medicine. 2013;6(2):305-9.
65. Zhao JH, Zhang WF, Zhao YF. Sclerotherapy of oral and facial venous malformations with use of pingyangmycin and/or sodium morrhuate. International journal of oral and maxillofacial surgery. 2004;33(5):463-6.
66. Zhong PQ, Zhi FX, Li R, Xue JL, Shu GY. Long-term results of intratumorous bleomycin-A5 injection for head and neck lymphangioma. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics. 1998;86(2):139-44.
67. Zulfiqar MA, Zaleha AM, Zakaria Z, Amin T. The treatment of neck lymphangioma with intralesional injection of bleomycin. The Medical journal of Malaysia. 1999;54(4):478-81.
|- Brief summary||In this pilot RCT, we will determine the feasibility and explore the efficacy and safety of electrosclerotherapy as a novel treatment option for capillary malformations. This is a method in which we combine intralesional injections with bleomycin with electroporation (= generating an electric field over the tissue). This is a double-blind (patient and outcome assessor) randomized within-patient controlled trial. All participants undergo one intervention session in which 3 homogeneous 1.5x1.5 cm parts of the capillary malformation are randomly allocated to  electrosclerotherapy,  bleomycin injection without electroporation or  no treatment. Outcome will be measured using patient- and outcome assessor-reported global changes in appearance using the validated POSAS score. Furthermore, adverse events will be reported. Changes in color and perfusion of the capillary malformation will be measured using colorimetry and optical imaging, respectively.|
|- Main changes (audit trail)|
|- RECORD||15-nov-2016 - 12-feb-2017|
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