Terapia Fotodinámica para manejo de la Enfermedad de Paget Vulvar.

Estudio habla sobre la metodología revisada en la literatura publicada.

Pr Serge Mordon (INSERM, Lille - France)

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Management of Extramammary Paget's disease with photodynamic therapy

Extramammary Paget's disease (EMPD) particularly involves the vulva, the perineal, perianal and axillary regions. The cutaneous lesions resemble those of mammary Paget's disease but where there is mucosal involvement, the lesions are more erosive and oozing. The main symptom is pruritus.

The benchmark treatment for all EMPD is based on surgical exeresis, as only the histological investigation of the whole surface of the lesion can rule out an invasive form, or an associated underlying adenocarcinoma requiring appropriate treatment. However there is no consensus on the resection margins 1. 

Even with control of the resection margins, the rates of local recurrence remain high of the order of 15% to 61% depending on the patient series, with functional and psychological sequelae.2, 3
This is probably linked to the multifocal nature of EMPD. A variety of other modalities been employed: topical and systemic chemotherapy, external radiotherapy, CO2 lasers, imiquimod, etc. The use of these therapies in combination has also been proposed but although numerous case reports have been published, all of these techniques have not been assessed in a systematic manner.

Photodynamic therapy (PDT) is itself also proposed as a therapeutic alternative and seems to offer beneficial levels of total remission with the disappearance of symptoms and a distinct improvement in the quality of life of patients.
Generally, the PDT protocol is similar to that offered for the treatment of actinic keratoses: application of a methyl aminolevulinic acid (MAL) cream followed three hours later by illumination with red light (570-670 nm) for 10 minutes at a dose of 37 J/cm². However, several sessions are conducted. The interval between each session varies greatly from one study to another.

The summary of several studies published on the subject shows a complete response after one year of the order of 50%. The symptoms and the quality of life are improved, even if this remains temporary. The main disadvantage of this technique is the pain during the PDT session (Table 1).

Table 1

Several teams are considering ways in which this technique could be improved in order to improve the response and the pain. The improvements could involve i) better application of 5-ALA in order to produce better distribution of the PpIX, ii) better illumination in order to guarantee a more homogeneous and reproducible light. Moreover, as natural daylight PDT shows, exposure to a less intense light for a longer time could also considerably reduce the pain.

Patch application

The prolonged application of the topical form of 5-ALA to the EMPD lesions, and to the vulva in particular, poses problems linked to the nature and structure of this particular site. The pharmacy faculty of Queen's University Belfast has developed an innovative bioadhesive patch intended for the vulva (Figure 1). This patch was formulated with a copolymer of methyl vinyl ether and maleic anhydride (PMVE/MA) as a bioadhesive matrix and poly(vinyl chloride) as a drug-impervious backing layer. This patch contains 38 mg/cm² of 5-ALA. 10

It has been tested with success in patients presenting with vulval Paget's disease where fluorescence measurements demonstrated that the application of 5-ALA was homogeneous and reproducible. Moreover, this patch is very easy to apply and to remove. 11. Clinical studies to assess its long-term efficacy are currently ongoing.

Illumination by means of light-emitting fabric

There are multiple light sources but the device most used in France is an LED panel emitting red light with a wavelength of 630 nm. Apart from the fact that these systems generate a powerful light intensity, causing intense pain in patients, they are not adapted to human anatomy and do not allow the whole lesion to be treated with homogeneous light (Figure 2).

With the aim of improving the quality of the light delivered, a fabric composed of woven optical fibers enabling the delivery of homogeneous light to all locations whatever the contours to be treated is currently being clinically assessed. 13, 14 As shown in Figure 3, this device can cover the entire area to be treated. It is comfortable and allows the treatment to be carried out over a longer time period (up to 2 hours) with lower irradiance levels. Using this new protocol, the pain is practically non-existent. A study is still ongoing but the device seems to be effective and to demonstrate excellent clinical tolerance.15

In conclusion, as emphasized by the team at University Hospital Limoges, "PDT enables extended periods of remission to be obtained without prejudice to functional or aesthetic elements, while improving patients' quality of life (functional symptoms and discomfort) with good patient acceptability and good levels of compliance with treatment. It offers a non-mutilating alternative that is part of a palliative strategy for recurrent EMPD and inoperable patients" 16. 

Having recourse to more suitable systems for the application of 5-ALA (patch) and for illuminating the area to be treated (light-emitting fabric) should allow the development of this therapeutic method.

References:

1- Renaud-Vimer C. http://www.therapeutique-dermatologique.org/spip.php?article1245, 2012

2- Housel JP, Izikson L, Zeitouni NC. Noninvasive extramammary Paget's disease treated with photodynamic therapy: case series from the Roswell Park Cancer Institute. Dermatol Surg. 2010 Nov;36(11):1718-24

3- Fanning J, Lambert HC, Hale TM, Morris PC, Schuerch C. Paget's disease of the vulva: prevalence of associated vulvar adenocarcinoma, invasive Paget's disease, and recurrence after surgical excision. Am J Obstet Gynecol 1999;180:24—7.

4- Housel JP, Izikson L, Zeitouni NC. Noninvasive extramammary Paget's disease treated with photodynamic therapy: case series from the Roswell Park Cancer Institute. Dermatol Surg. 2010 Nov;36(11):1718-24

5- Gao Y, Zhang XC, Wang WS, Yang Y, Wang HL, Lu YG, Fan DL. Efficacy and safety of topical ALA-PDT in the treatment of EMPD. Photodiagnosis Photodyn Ther.2015Mar;12(1):92-7. doi: 10.1016

6- Jing W, Juan X, Li X, Jiayuan C, Qin H, Qing L, Shengmei X. Complete remission of two patients with recurrent and wide spread extramammary Paget disease obtained from 5-aminolevulinic acid-based photodynamic therapy and imiquimod combination treatment. Photodiagnosis Photodyn Ther. 2014 Sep;11(3):434-40.

7- Wang HW, Lv T, Zhang LL, Lai YX, Tang L, Tang YC, Huang Z, Wang XL. A prospective pilot study to evaluate combined topical photodynamic therapy and surgery for extramammary paget's disease. Lasers Surg Med. 2013 Jul;45(5):296-301.

8- Fontanelli R, Papadia A, Martinelli F, Lorusso D, Grijuela B, Merola M, Solima E, Ditto A, Raspagliesi F. Photodynamic therapy with M-ALA as non surgical treatment option in patients with primary extramammary Paget's disease. Gynecol Oncol. 2013 Jul;130(1):90-4.

9- Clément E, Sparsa A, Doffoel-Hantz V, Durox H, Prey S, Bonnetblanc JM, Caly H, Aubard Y, Bedane C. Traitement de la maladie de Paget extramammaire par photothérapie dynamique topique. Ann Dermatol Venereol. 2012 Feb;139(2):103-8.

10- McCarron PA, Donnelly RF, Zawislak A, Woolfson AD, Price JH, McClelland R.Evaluation of a water-soluble bioadhesive patch for photodynamic therapy of vulval lesions. Int J Pharm. 2005 Apr 11;293(1-2):11-23.

11- Zawislak AA, McCarron PA, McCluggage WG, Price JH, Donnelly RF, McClelland HR,Dobbs SP, Woolfson AD. Successful photodynamic therapy of vulval Paget's disease using a novel patch-based delivery system containing 5-aminolevulinic acid. BJOG.2004 Oct;111(10):1143-5.

12- Zawislak A, Donnelly RF, McCluggage WG, Price JH, McClelland HR, Woolfson AD, Dobbs S, Maxwell P, McCarron PA. Clinical and immunohistochemical assessment of vulval intraepithelial neoplasia following photodynamic therapy using a novel bioadhesive patch-type system loaded with 5-aminolevulinic acid. Photodiagnosis Photodyn Ther. 2009 Mar;6(1):28-40.

13- Cochrane C, Mordon SR, Lesage JC, Koncar V. New design of textile light diffusers for photodynamic therapy. Mater Sci Eng C Mater Biol Appl. 2013 Apr 1;33(3):1170-5

14- Mordon S, Cochrane C, Tylcz JB, Betrouni N, Mortier L, Koncar V. Light emitting fabric technologies for photodynamic therapy. Photodiagnosis Photodyn Ther. 2015 Mar;12(1):1-8.

15- Vicentini C. Carpentier O., Tylcz JB, , Betrouni N., .Mortier L., Mordon S. Treatment of a vulvar paget disease by photodynamic therapy with a new light emitting fabric based device. Lasers in Surgery and Medicine, 2016, 48, S 27, 180:61

16- Clément E, Sparsa A, Doffoel-Hantz V, Durox H, Prey S, Bonnetblanc JM, Caly H, Aubard Y, Bedane C. Photodynamic therapy for the treatment of extramammary Paget's disease]. Ann Dermatol Venereol. 2012 Feb;139(2):103-8.