- Email: [email protected]
Photodynamic therapy with green light for the treatment of vulvar lichen sclerosus – Preliminary results
Accepted Manuscript Title: PHOTODYNAMIC THERAPY WITH GREEN LIGHT FOR THE TREATMENT OF VULVAR LICHEN SCLEROSUS − PRELIMINARY RESULTS Author: B.J. Osiecka K. Jurczyszyn P. Nockowski M Murawski P. Zi´ołkowski PII: DOI: Reference:
S1572-1000(16)30090-4 http://dx.doi.org/doi:10.1016/j.pdpdt.2016.11.015 PDPDT 863
To appear in:
Photodiagnosis and Photodynamic Therapy
Received date: Revised date: Accepted date:
30-5-2016 14-11-2016 29-11-2016
Please cite this article as: Osiecka BJ, Jurczyszyn K, Nockowski P, Murawski M, Zi´ołkowski P.PHOTODYNAMIC THERAPY WITH GREEN LIGHT FOR THE TREATMENT OF VULVAR LICHEN SCLEROSUS − PRELIMINARY RESULTS.Photodiagnosis and Photodynamic Therapy http://dx.doi.org/10.1016/j.pdpdt.2016.11.015 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Highlights
Photodynamic therapy is a good therapeutic option in chronic vulvar lichen sclerosus.
The disadvantage of the red light is severe local pain during the illumination.
Efficacy and tolerance of photodynamic therapy with green light was evaluated.
The sessions of irradiation were good tolerate without intense pain.
Symptoms improvement for all patients was stable over 6 months for 7 of 11 ones.
PHOTODYNAMIC THERAPY WITH GREEN LIGHT
FOR THE
TREATMENT OF VULVAR LICHEN SCLEROSUS – PRELIMINARY RESULTS.
B. J. OsieckaA, K. JurczyszynB, P. NockowskiC, M MurawskiD, P. ZiółkowskiA
A - Department of Pathology, Wroclaw Medical University, Wroclaw, Poland, B – Department of Oral Surgery, Wroclaw Medical University, Wroclaw, Poland, C - Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland, D - Ist Department of Gynaecology and Obstetrics, Wroclaw Medical University, Wroclaw, Poland
Corresponding author: Piotr Nockowski; Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, ul. Chalubinskiego 1, 50-368 Wroclaw, Poland; Tel. 071/784-22-86, Fax. 071/327-09-42, e-mail: [email protected]
Running head: PDT with green light for the treatment of LS
Abstract Introduction: The standard treatment for lichen sclerosus (LS) is symptomatic and is primarily based on the chronic use of corticosteroids, sometimes resulting in unsatisfactory effects. Therefore, other non-pharmacological methods are being sought, which are less aggravating for the patient. LS can be treated topically by using photodynamic therapy (PDT) based on 5-aminolevulinic acid (5-ALA). Unfortunately, therapy with the red light is often connected with severe local pain during the illumination. Green light can also be characterised by its ability to turn on photodynamic reactions in cells. Materials and methods: The aim of this study was an evaluation into the efficacy and tolerance of 5ALA-PDT with a green light (540 nm ± 15 nm) in 11 patients with chronic LS that were characterised by severe itching. The disease lasted from 1.5 to 4 years. All the patients were treated with three sessions of PDT. Results: Following treatment with PDT, a significant improvement of local status, as well as a reduction of the main symptom (pruritus), were observed. No patient complained of severe pain during the sessions that would have required an interruption of irradiation or local application of analgesics. Conclusions: Our preliminary results of using green light in PDT for superficial skin non-oncological lesions are very promising but require further studies.
Key words: photodynamic therapy; green light; 5-aminolevulinic acid; vulvar lichen sclerosus
Introduction Lichen sclerosus (LS - formerly "lichen sclerosus et atrophicus") of the vulva is a chronic inflammatory disease of unknown aetiology. Fully symptomatic vulvar LS is recognised by irreversible white atrophic changes in the vulvar skin and mucosa, accompanied by erosions and fissures, intensive itching, burning and pain. It causes sexual dysfunction as well as a deterioration in the quality of life [1]. LS mainly affects women in their postmenopausal stage and may lead to squamous cell carcinoma of the vulva [2]. Standard pharmacotherapy is symptomatic and comprises mainly of a local administration of corticosteroids, topical calcineurin inhibitors, topical testosterone, estrogens, retinoids and cryotherapy [2,3,4]. The effectiveness of therapy with ultrapotent topical corticosteroids is best evidenced. It allows complete relief of symptoms in about 70%, and complete remission of skin changes in 20% of vulvar LS patients [1]. However, it means, that for about 30% of women the effect of such therapy is unsatisfactory. Moreover, long-term maintenance treatment is later needed to avoid a relapse and prolonged application may result in various side effects. Alternatively, LS can be treated by using photodynamic therapy (PDT) [5,6,7,8,9]. In contrast to many conventional therapeutic modalities employed against LS, the side effects for PDT are comparatively few and transient [10]. The most commonly used compound is 5-aminolevulinic acid (5-ALA) with a red light (with a maximum at 630- 635 nm regarding the used light source), which induces photochemical reactions in tissues. This therapeutic method is helpful even with chronic, recalcitrant and unresponsive to pharmacological and surgical treatment cases of vulvar LS [8], but PDT seems to have a greater effect on the alleviation of subjective symptoms than on the relief of clinical lesions [7,9]. Unfortunately, it is often connected with severe local pains during the illumination, which infrequently leads to patients resigning from this therapy [10,11]. A limited number of literature data reported that an application of a green light (495-570 nm) is effective and less painful in frames of PDT in precancerous lesions of the skin [12,13]. However, some scientific reports indicate that a green light is less effective and is comparatively as painful as the red light at a theoretically equivalent dose [14]. We did not find any literature, where PDT with a green light has been applied
to treat inflammatory, non-oncologic dermatoses, except for a few small clinical types of research using the new photosensitizer indole-3-acetic acid (IAA) in acne vulgaris and seborrhoeic dermatitis [15,16] The aim of this study was to evaluate the efficacy and tolerance of 5-ALA-PDT with a green light in patients with chronic vulvar LS.
Material and methods The clinical study was approved by its local ethics committee (KB-6/2014). Patients gave their informed consent before enrolment. The study comprised of 11 patients with LS of the vulva, confirmed by a routine histopathologic examination. The age of patients ranged from 30 to 66 years (mean: 48). The disease lasted from 1.5 to 4 years. The patients were pharmacologically treated in the past with various methods, and all were chronically treated with topical corticosteroids, estrogens, and calcineurin inhibitors, however, no satisfactory effect was obtained. Physically, in all patients, the vulvar region showed white scarring-like areas. The degree of pruritus was evaluated before treatment and after 2, 4, and 6 months from PDT using a verbal rating scale (VRS): lack, weak, moderate or severe. In order to visualise the pathologic lesions prior to PDT, a photodynamic diagnosis (PDD) was performed. Topical 5% 5-ALA (Sigma-Aldrich) was used in each case. After 3.5 hours, the vulva was illuminated with a blue light (405 nm) from a halogen light source (Penta Lamps, Teclas), in order to obtain the red fluorescence of the lesions. PDD was accomplished in confirming the activity of the disease without further specific evaluation. On the following day, after cleansing the area with 0.9% saline solution, 20% 5-ALA (SigmaAldrich) in a cream (Nanobase®, Astellas Pharma) was applied topically on the lesions with a wide margin beyond the affected area, sealed with cellophane wrap and left for 5 hours. Then, the vulva was irradiated using the green light at the wavelength 540 nm ± 15 nm from the halogen lamp (Penta Lamps, Teclas) achieved with a bandpass filter, according to Fritsch et al. [12]. There is no single approved standard protocol for PDT in LS [5,6,7,9]. In our study, each patient was treated with three
sessions of PDT at two-week intervals. Dosimetry of the light applied to PDT (85 mW/cm2, and 62.5 J/ cm2) was adapted from the literature data, calculated for the green light (540 nm) where the fluence 62.5 J/ cm2 (green light) corresponds to fluence 125 J/ cm2 for the red light (630 nm) [14]. The irradiation was performed in a fractionated mode during each session: two minutes of irradiation and one-minute pause. After three sessions of PDT, patients were examined every two months for half a year.
Results Before the PDT treatment, all 11 patients complained of chronic itching of the vulva, scored with verbal rating scale as moderate to severe. Erosions were observed in five women accompanied with burning sensations and in three women with pain (Table 1). PDD fluorescence occurred by all patients within the area affected by the LS lesion as evaluated visually under white light. Most of the fluorescent foci were smaller than the area of visible lesions, but in some patients the fluorescence partially occurred outside the clinical changes. During PDD patients did not report any pain or other sensations. All patients finished the entire therapy. The main symptom during PDT notified by patients was an itching of different intensity. Any reported pain was weak or moderate. No patient required interruption of irradiation or local application of analgesics. Furthermore, immediately after the session of PDT we observed a slight swelling and erythema, which was not a significant side symptom reported by the patients. Following PDT, a significant improvement of local status was observed (Table 2). After two months from PDT, erosions disappeared in all five patients (100%), who primarily had erosions in the vulvar region. The erosions recurred after four months from PDT in one woman, and in two after 6 months, which were accompanied with burning sensations. Within two months after PDT itching subsided in nine patients (81.8%), one patient reported weak itching and one reported moderate. No itching was observed in eight patients (72.7%) within four months after PDT and seven women
(63.6%) still notified no itching after six months. Within six months’ observation, three patients reported a weak itching mainly before menstruation. One woman complained of moderate itching within the whole period of observation after PDT.
Discussion PDT seems to be an alternative method of LS treatment, especially in patients with intense itching or contraindications to steroid-based therapy. The efficacy of local 5-ALA-PDT by means of the red light was often confirmed in the past. Hillemanns et al. achieved smoothening of itching and alleviation of pain in 10 of 12 women with LS for six months [7]. Patients were treated during 1, 2 or 3 sessions of PDT with 5-ALA and irradiation with a 635-argon dye laser. Very intense symptoms which accompanied irradiation (burning pain) were relieved by the means of intravenous application of analgesics in three women, and in one patient – general anaesthesia [7]. Zawislak et al. also observed the good clinical response to the 5-ALA-PDT of vulvar LS after one or two sessions of irradiation at 630 nm. An intense burning and pain also prompted them to use local anaesthesia [17]. Although the perception of pain is a very individual feature, some literature data indicates that a stinging pain during illumination by PDT seems to be a serious problem, which prompted a number of patients to resign from the therapy [10,11,18]. Red light is mainly used in PDT considering its deep penetration in tissues, what is especially important in the treatment of precancerous skin lesions as well as skin cancer. PDT was also applied to many non-oncologic disorders of the skin because this therapy affects the immune response, inflammatory reactions, and blood vessels [19]. LS is a chronic, inflammatory disease which begins on dermal- epidermal junction. The green light penetrates tissues and acts more superficially than the red light, but hypothetically, it can be less painful during the irradiation. The green light was first used in topical 5-ALA-PDT by Fritsch et al. who successfully treated six patients with actinic keratosis. They found that the irradiation with a green light was less burdensome and less painful in
comparison to a red light [12]. Morton et al. observed slightly better tolerances with a green light by patients being treated due to Bowen disease [14]. In a wider scope of the literature, pain perception differs widely between patients and the correlation of pain with various parameters of ALA-PDT (inclusive wavelength of light) are not consistent [20]. The phenomenon of burning pain during PDT is still not clarified. The mostly likely explanation refers to nerve stimulation and/or tissue damage by reactive oxygen species. It can be presumed, that shallower penetration of the green light may not include all the nerve endings and receptors located at different levels of the dermis. In this paper, we present the preliminary report on the application of green light in PDT of vulvar LS in patients with intense itching or patients which do not respond to standard pharmacotherapy. The number of patients is small and except itching as the predominant symptom, other symptoms occurred in individual patients. Therefore, we did not include a gradation of other symptoms and their statistical analysis. The work was focused on eliminating the main symptom pruritus using PDT with parameters acceptable to the patient. We found that irradiation of vulvar LS during three sessions was not disturbed by pain reactions and was accepted by all patients. The main complaint reported during irradiation was the itching of variable intensity. Beside a good tolerance of PDT during irradiations, after three sessions the main aim of the therapy was accomplished: the dominating symptom – itching – disappeared or was reduced in most patients and the temporary disappearance of erosions was observed. This allowed a possibility for repetition of PDT if the patient finds a need for it, due to the recurrence of intolerable symptoms. However, none of the studied patients has offered themselves for retreatment after the follow-up period. The therapeutic effects attained in our study could probably be attributed to several factors, like a high concentration of 5-ALA (20%), the longer application time of 5-ALA before irradiation (5 hours) and fractionated method of light delivery (2 minutes of irradiation and 1-minute pause). The explanation of the role of above factors requires further extended studies.
We conclude that the advantage of this modification of PDT is good tolerance of irradiations without intense pain, which is the common side effect when using the red light. Our preliminary results of using green light in PDT in the case of non-oncologic skin lesions, presumably in superficial inflammatory disorders of the skin are very promising but require further studies.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
References: [1] S.K. Fistarol, P.H. Itin, Diagnosis and treatment of lichen sclerosus: an update. Am J Clin Dermatol. 14 (2013) 27-47. [2] C.C. Chi, G. Kirtschig, M. Baldo, F. Lewis, S.H. Wang,F. Wojnarowska, Systematic review and metaanalysis of randomized controlled trials on topical interventions for genital lichen sclerosus. J Am Acad Dermatol. 67 (2012) 305-312. [3] J.M. Pugliese, A.F. Morey, A.C. Peterson, Lichen sclerosus: review of the literature and current recommendations for management. J Urol. 178 (2007) 2268-2276. [4] A. Sadowska-Przytocka, A. Dańczak-Pazdrowska, A. Szewczyk, M. Czarnecka-Operacz, D. Jenerowicz, A. Osmola-Mańkowska, K. Olek-Hrab, Treatment of genital lichen sclerosus in women review. Ginekol Pol. 83 (2012) 458-461. [5] A. Olejek, I. Kozak-Darmas, S. Kellas-Sleczka, K. Steplewska, T. Biniszkiewicz, B. Birkner, A. Jarek, L. Nowak, K. Stencel-Gabriel, A. Sieron, Effectiveness of photodynamic therapy in the treatment of lichen sclerosus: cell changes in immunohistochemistry. Neuro Endocrinol Lett. 30 (2009) 547-551. [6] B.J. Osiecka, P. Nockowski, K. Jurczyszyn, P. Ziólkowski, Photodynamic therapy of vulvar lichen sclerosus et atrophicus in a woman with hypothyreosis--case report. Photodiagnosis Photodyn Ther. 9 (2012) 186-188. [7] P. Hillemanns, M. Untch, F. Próve, R. Baumgartner, M. Hillemanns, M. Korell, Photodynamic therapy of vulvar lichen sclerosus with 5-aminolevulinic acid. Obstet Gynecol 93 (1999) 71-74. [8] A. Romero, A. Hernández-Núñez, S. Córdoba-Guijarro, D. Arias-Palomo, J. Borbujo-Martínez, Treatment of recalcitrant erosive vulvar lichen sclerosus with photodynamic therapy. J Am Acad Dermatol.57 Suppl 2 ( 2007) S46-47. [9] E. Sotiriou, D. Panagiotidou, D. Ioannidis D, An open trial of 5-aminolevulinic acid photodynamic therapy for vulvar lichen sclerosus. Eur J Obstet Gynecol Reprod Biol. 141 (2008) 187-188. [10] P. Lehmann, Side effects of topical photodynamic therapy. Hautarzt. 58 (2007) 597-603. [11] A.M. Wennberg, Pain, pain relief and other practical issues in photodynamic therapy. Australas J Dermatol. 46 Suppl 3 (2005) S3-4; discussion S23-S25. [12] C. Fritsch, H. Stege, G. Saalmann, G. Goerz, T. Ruzicka, J. Krutmann, Green light is effective and less painful than red light in photodynamic therapy of facial solar keratoses. Photodermatol Photoimmunol Photomed. 13 (1997) 181-185. [13] M. Triesscheijn, P. Baasa, J. Schellensa, F. Stewart, Photodynamic Therapy in Oncology. The Oncologist October 11 (2006) 1034-1044. [14] C.A. Morton, C. Whitehurst, J.V. Moore, R.M. MacKie, Comparison of red and green light in the treatment of Bowen's disease by photodynamic therapy.Br J Dermatol. 143 (2000) 767-772. [15] W. Zheng , Y. Wu, X. Xu, X. Gao, H.D. Chen, Y. Li, Evidence-based review of photodynamic therapy in the treatment of acne. Eu J Dermatol 24 (2014) 444-456. [16] S.H. Kwon, M.Y. Jeong, K.C. Park, S.W. Youn, C.H. Huh, J.I. Na, A new therapeutic option for facial seborrhoeic dermatitis: indole-3-acetic acid photodynamic therapy. J Eur Acad Dermatol Venereol 28 (2014) 94-99. [17] A.A. Zawislak, W.G. McCluggage, R.F. Donnelly, P. Maxwell , J.H. Price, S.P. Dobbs, H.R. McClelland, A.D. Woolfson, P.A. Mccarron, Response of vulval lichen sclerosus and squamous hyperplasia to photodynamic treatment using sustained topical delivery of aminolevulinic acid from a novel bioadhesive patch system. Photodermatol Photoimmunol Photomed. 25 (2009) 111-113.
[18] F. Cairnduff, M.R. Stringer, E.J. Hudson, D.V. Ash, S.B. Brown, Superficial photodynamic therapy with topical 5-aminolaevulinic acid for superficial primary and secondary skin cancer. Br J Cancer. 69 (1994) 605-608. [19] H. Wang, J. Li, T. Lv, Q. Tu, Z. Huang, X. Wang, Therapeutic and immune effects of 5aminolevulinic acid photodynamic therapy on UVB-induced squamous cell carcinomas in hairless mice. Exp Dermatol. 22 (2013) 362-363. [20] C.B. Warren, L.J. Karai, A. Vidimos, E.V. Maytin, Pain Associated with Aminolevulinic AcidPhotodynamic Therapy of Skin Disease. J Am Acad Dermatol. 61 (2009) 1033-1043.
Table 1. Symptoms occurring in patients with vulvar LS prior to the PDT.
No. patients
itching (VRS score)
Burning
erosions
pain
lack
weak
moderate
severe
11
0
0
4
7
5
5
3
%
0
0
36.4
63.6
45.5
45.5
27.3
Table 2. Effects of therapy of vulvar LS with 5-ALA and green light in 2 month intervals (after 2, 4 and 6 months from PDT)
Effect after 2 months from PDT No. patients lack
itching (VRS score) weak moderate severe
burning
erosions
pain
11
9
1
1
0
0
0
1
%
81.8
9.1
9.1
0.0
0.0
0.0
9.1
burning
erosions
pain
Effect after 4 months from PDT No. patients
itching lack
weak
moderate
severe
11
8
2
1
0
1
1
1
%
72.7
18.2
9.1
0.0
9.1
9.1
9.1
burning
erosions
pain
Effect after 6 months from PDT No. patients
itching lack
weak
moderate
severe
11
7
3
1
0
2
2
2
%
63.6
27.3
9.1
0.0
18.2
18.2
18.2
S1572-1000(16)30090-4 http://dx.doi.org/doi:10.1016/j.pdpdt.2016.11.015 PDPDT 863
To appear in:
Photodiagnosis and Photodynamic Therapy
Received date: Revised date: Accepted date:
30-5-2016 14-11-2016 29-11-2016
Please cite this article as: Osiecka BJ, Jurczyszyn K, Nockowski P, Murawski M, Zi´ołkowski P.PHOTODYNAMIC THERAPY WITH GREEN LIGHT FOR THE TREATMENT OF VULVAR LICHEN SCLEROSUS − PRELIMINARY RESULTS.Photodiagnosis and Photodynamic Therapy http://dx.doi.org/10.1016/j.pdpdt.2016.11.015 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Highlights
Photodynamic therapy is a good therapeutic option in chronic vulvar lichen sclerosus.
The disadvantage of the red light is severe local pain during the illumination.
Efficacy and tolerance of photodynamic therapy with green light was evaluated.
The sessions of irradiation were good tolerate without intense pain.
Symptoms improvement for all patients was stable over 6 months for 7 of 11 ones.
PHOTODYNAMIC THERAPY WITH GREEN LIGHT
FOR THE
TREATMENT OF VULVAR LICHEN SCLEROSUS – PRELIMINARY RESULTS.
B. J. OsieckaA, K. JurczyszynB, P. NockowskiC, M MurawskiD, P. ZiółkowskiA
A - Department of Pathology, Wroclaw Medical University, Wroclaw, Poland, B – Department of Oral Surgery, Wroclaw Medical University, Wroclaw, Poland, C - Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland, D - Ist Department of Gynaecology and Obstetrics, Wroclaw Medical University, Wroclaw, Poland
Corresponding author: Piotr Nockowski; Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, ul. Chalubinskiego 1, 50-368 Wroclaw, Poland; Tel. 071/784-22-86, Fax. 071/327-09-42, e-mail: [email protected]
Running head: PDT with green light for the treatment of LS
Abstract Introduction: The standard treatment for lichen sclerosus (LS) is symptomatic and is primarily based on the chronic use of corticosteroids, sometimes resulting in unsatisfactory effects. Therefore, other non-pharmacological methods are being sought, which are less aggravating for the patient. LS can be treated topically by using photodynamic therapy (PDT) based on 5-aminolevulinic acid (5-ALA). Unfortunately, therapy with the red light is often connected with severe local pain during the illumination. Green light can also be characterised by its ability to turn on photodynamic reactions in cells. Materials and methods: The aim of this study was an evaluation into the efficacy and tolerance of 5ALA-PDT with a green light (540 nm ± 15 nm) in 11 patients with chronic LS that were characterised by severe itching. The disease lasted from 1.5 to 4 years. All the patients were treated with three sessions of PDT. Results: Following treatment with PDT, a significant improvement of local status, as well as a reduction of the main symptom (pruritus), were observed. No patient complained of severe pain during the sessions that would have required an interruption of irradiation or local application of analgesics. Conclusions: Our preliminary results of using green light in PDT for superficial skin non-oncological lesions are very promising but require further studies.
Key words: photodynamic therapy; green light; 5-aminolevulinic acid; vulvar lichen sclerosus
Introduction Lichen sclerosus (LS - formerly "lichen sclerosus et atrophicus") of the vulva is a chronic inflammatory disease of unknown aetiology. Fully symptomatic vulvar LS is recognised by irreversible white atrophic changes in the vulvar skin and mucosa, accompanied by erosions and fissures, intensive itching, burning and pain. It causes sexual dysfunction as well as a deterioration in the quality of life [1]. LS mainly affects women in their postmenopausal stage and may lead to squamous cell carcinoma of the vulva [2]. Standard pharmacotherapy is symptomatic and comprises mainly of a local administration of corticosteroids, topical calcineurin inhibitors, topical testosterone, estrogens, retinoids and cryotherapy [2,3,4]. The effectiveness of therapy with ultrapotent topical corticosteroids is best evidenced. It allows complete relief of symptoms in about 70%, and complete remission of skin changes in 20% of vulvar LS patients [1]. However, it means, that for about 30% of women the effect of such therapy is unsatisfactory. Moreover, long-term maintenance treatment is later needed to avoid a relapse and prolonged application may result in various side effects. Alternatively, LS can be treated by using photodynamic therapy (PDT) [5,6,7,8,9]. In contrast to many conventional therapeutic modalities employed against LS, the side effects for PDT are comparatively few and transient [10]. The most commonly used compound is 5-aminolevulinic acid (5-ALA) with a red light (with a maximum at 630- 635 nm regarding the used light source), which induces photochemical reactions in tissues. This therapeutic method is helpful even with chronic, recalcitrant and unresponsive to pharmacological and surgical treatment cases of vulvar LS [8], but PDT seems to have a greater effect on the alleviation of subjective symptoms than on the relief of clinical lesions [7,9]. Unfortunately, it is often connected with severe local pains during the illumination, which infrequently leads to patients resigning from this therapy [10,11]. A limited number of literature data reported that an application of a green light (495-570 nm) is effective and less painful in frames of PDT in precancerous lesions of the skin [12,13]. However, some scientific reports indicate that a green light is less effective and is comparatively as painful as the red light at a theoretically equivalent dose [14]. We did not find any literature, where PDT with a green light has been applied
to treat inflammatory, non-oncologic dermatoses, except for a few small clinical types of research using the new photosensitizer indole-3-acetic acid (IAA) in acne vulgaris and seborrhoeic dermatitis [15,16] The aim of this study was to evaluate the efficacy and tolerance of 5-ALA-PDT with a green light in patients with chronic vulvar LS.
Material and methods The clinical study was approved by its local ethics committee (KB-6/2014). Patients gave their informed consent before enrolment. The study comprised of 11 patients with LS of the vulva, confirmed by a routine histopathologic examination. The age of patients ranged from 30 to 66 years (mean: 48). The disease lasted from 1.5 to 4 years. The patients were pharmacologically treated in the past with various methods, and all were chronically treated with topical corticosteroids, estrogens, and calcineurin inhibitors, however, no satisfactory effect was obtained. Physically, in all patients, the vulvar region showed white scarring-like areas. The degree of pruritus was evaluated before treatment and after 2, 4, and 6 months from PDT using a verbal rating scale (VRS): lack, weak, moderate or severe. In order to visualise the pathologic lesions prior to PDT, a photodynamic diagnosis (PDD) was performed. Topical 5% 5-ALA (Sigma-Aldrich) was used in each case. After 3.5 hours, the vulva was illuminated with a blue light (405 nm) from a halogen light source (Penta Lamps, Teclas), in order to obtain the red fluorescence of the lesions. PDD was accomplished in confirming the activity of the disease without further specific evaluation. On the following day, after cleansing the area with 0.9% saline solution, 20% 5-ALA (SigmaAldrich) in a cream (Nanobase®, Astellas Pharma) was applied topically on the lesions with a wide margin beyond the affected area, sealed with cellophane wrap and left for 5 hours. Then, the vulva was irradiated using the green light at the wavelength 540 nm ± 15 nm from the halogen lamp (Penta Lamps, Teclas) achieved with a bandpass filter, according to Fritsch et al. [12]. There is no single approved standard protocol for PDT in LS [5,6,7,9]. In our study, each patient was treated with three
sessions of PDT at two-week intervals. Dosimetry of the light applied to PDT (85 mW/cm2, and 62.5 J/ cm2) was adapted from the literature data, calculated for the green light (540 nm) where the fluence 62.5 J/ cm2 (green light) corresponds to fluence 125 J/ cm2 for the red light (630 nm) [14]. The irradiation was performed in a fractionated mode during each session: two minutes of irradiation and one-minute pause. After three sessions of PDT, patients were examined every two months for half a year.
Results Before the PDT treatment, all 11 patients complained of chronic itching of the vulva, scored with verbal rating scale as moderate to severe. Erosions were observed in five women accompanied with burning sensations and in three women with pain (Table 1). PDD fluorescence occurred by all patients within the area affected by the LS lesion as evaluated visually under white light. Most of the fluorescent foci were smaller than the area of visible lesions, but in some patients the fluorescence partially occurred outside the clinical changes. During PDD patients did not report any pain or other sensations. All patients finished the entire therapy. The main symptom during PDT notified by patients was an itching of different intensity. Any reported pain was weak or moderate. No patient required interruption of irradiation or local application of analgesics. Furthermore, immediately after the session of PDT we observed a slight swelling and erythema, which was not a significant side symptom reported by the patients. Following PDT, a significant improvement of local status was observed (Table 2). After two months from PDT, erosions disappeared in all five patients (100%), who primarily had erosions in the vulvar region. The erosions recurred after four months from PDT in one woman, and in two after 6 months, which were accompanied with burning sensations. Within two months after PDT itching subsided in nine patients (81.8%), one patient reported weak itching and one reported moderate. No itching was observed in eight patients (72.7%) within four months after PDT and seven women
(63.6%) still notified no itching after six months. Within six months’ observation, three patients reported a weak itching mainly before menstruation. One woman complained of moderate itching within the whole period of observation after PDT.
Discussion PDT seems to be an alternative method of LS treatment, especially in patients with intense itching or contraindications to steroid-based therapy. The efficacy of local 5-ALA-PDT by means of the red light was often confirmed in the past. Hillemanns et al. achieved smoothening of itching and alleviation of pain in 10 of 12 women with LS for six months [7]. Patients were treated during 1, 2 or 3 sessions of PDT with 5-ALA and irradiation with a 635-argon dye laser. Very intense symptoms which accompanied irradiation (burning pain) were relieved by the means of intravenous application of analgesics in three women, and in one patient – general anaesthesia [7]. Zawislak et al. also observed the good clinical response to the 5-ALA-PDT of vulvar LS after one or two sessions of irradiation at 630 nm. An intense burning and pain also prompted them to use local anaesthesia [17]. Although the perception of pain is a very individual feature, some literature data indicates that a stinging pain during illumination by PDT seems to be a serious problem, which prompted a number of patients to resign from the therapy [10,11,18]. Red light is mainly used in PDT considering its deep penetration in tissues, what is especially important in the treatment of precancerous skin lesions as well as skin cancer. PDT was also applied to many non-oncologic disorders of the skin because this therapy affects the immune response, inflammatory reactions, and blood vessels [19]. LS is a chronic, inflammatory disease which begins on dermal- epidermal junction. The green light penetrates tissues and acts more superficially than the red light, but hypothetically, it can be less painful during the irradiation. The green light was first used in topical 5-ALA-PDT by Fritsch et al. who successfully treated six patients with actinic keratosis. They found that the irradiation with a green light was less burdensome and less painful in
comparison to a red light [12]. Morton et al. observed slightly better tolerances with a green light by patients being treated due to Bowen disease [14]. In a wider scope of the literature, pain perception differs widely between patients and the correlation of pain with various parameters of ALA-PDT (inclusive wavelength of light) are not consistent [20]. The phenomenon of burning pain during PDT is still not clarified. The mostly likely explanation refers to nerve stimulation and/or tissue damage by reactive oxygen species. It can be presumed, that shallower penetration of the green light may not include all the nerve endings and receptors located at different levels of the dermis. In this paper, we present the preliminary report on the application of green light in PDT of vulvar LS in patients with intense itching or patients which do not respond to standard pharmacotherapy. The number of patients is small and except itching as the predominant symptom, other symptoms occurred in individual patients. Therefore, we did not include a gradation of other symptoms and their statistical analysis. The work was focused on eliminating the main symptom pruritus using PDT with parameters acceptable to the patient. We found that irradiation of vulvar LS during three sessions was not disturbed by pain reactions and was accepted by all patients. The main complaint reported during irradiation was the itching of variable intensity. Beside a good tolerance of PDT during irradiations, after three sessions the main aim of the therapy was accomplished: the dominating symptom – itching – disappeared or was reduced in most patients and the temporary disappearance of erosions was observed. This allowed a possibility for repetition of PDT if the patient finds a need for it, due to the recurrence of intolerable symptoms. However, none of the studied patients has offered themselves for retreatment after the follow-up period. The therapeutic effects attained in our study could probably be attributed to several factors, like a high concentration of 5-ALA (20%), the longer application time of 5-ALA before irradiation (5 hours) and fractionated method of light delivery (2 minutes of irradiation and 1-minute pause). The explanation of the role of above factors requires further extended studies.
We conclude that the advantage of this modification of PDT is good tolerance of irradiations without intense pain, which is the common side effect when using the red light. Our preliminary results of using green light in PDT in the case of non-oncologic skin lesions, presumably in superficial inflammatory disorders of the skin are very promising but require further studies.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Table 1. Symptoms occurring in patients with vulvar LS prior to the PDT.
No. patients
itching (VRS score)
Burning
erosions
pain
lack
weak
moderate
severe
11
0
0
4
7
5
5
3
%
0
0
36.4
63.6
45.5
45.5
27.3
Table 2. Effects of therapy of vulvar LS with 5-ALA and green light in 2 month intervals (after 2, 4 and 6 months from PDT)
Effect after 2 months from PDT No. patients lack
itching (VRS score) weak moderate severe
burning
erosions
pain
11
9
1
1
0
0
0
1
%
81.8
9.1
9.1
0.0
0.0
0.0
9.1
burning
erosions
pain
Effect after 4 months from PDT No. patients
itching lack
weak
moderate
severe
11
8
2
1
0
1
1
1
%
72.7
18.2
9.1
0.0
9.1
9.1
9.1
burning
erosions
pain
Effect after 6 months from PDT No. patients
itching lack
weak
moderate
severe
11
7
3
1
0
2
2
2
%
63.6
27.3
9.1
0.0
18.2
18.2
18.2