Journal of Cosmetic and Laser Therapy
ISSN: 1476-4172 (Print) 1476-4180 (Online) Journal homepage: http://www.tandfonline.com/loi/ijcl20
Light emitting diodes in photodynamic therapy in non-melanoma skin cancers – own observations and literature review Anna Erkiert-Polguj, Adam Halbina, Izabela Polak-Pacholczyk & Helena Rotsztejn To cite this article: Anna Erkiert-Polguj, Adam Halbina, Izabela Polak-Pacholczyk & Helena Rotsztejn (2016): Light emitting diodes in photodynamic therapy in non-melanoma skin cancers – own observations and literature review, Journal of Cosmetic and Laser Therapy, DOI: 10.3109/14764172.2015.1114635 To link to this article: http://dx.doi.org/10.3109/14764172.2015.1114635
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Just Accepted by Journal of Cosmetic and Laser Therapy
Light emitting diodes in photodynamic therapy in non-melanoma skin cancers – own observations and literature review Anna Erkiert-Polguj, Adam Halbina, Izabela Polak-Pacholczyk, Helena Rotsztejn Doi: 10.3109/14764172.2015.1114635
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Abstract Photodynamic therapy (PDT) employs light activation of tissue-localized photosensitizer in an oxygen-dependent process which initiates oxidative stress, inflammation and cell death. There are many indications for PDT, although the main ones are still non-melanoma skin cancers. Used light sources include coherent and non-coherent ones, but we would like to focus on the use of light-emitting diodes (LED) in PDT. We present four patients with skin lesions successfully treated with LED-based photodynamic therapy. The main advantage of that source is narrow emission spectrum that can correspond well with photosensitizers maximum absorption. Also, using LED source seems to be cheaper and simpler, and the field of irradiation is larger. The data showed good clinical and cosmetic outcome of LEDbased PDT in actinic keratosis, basal cell carcinoma, Bowen’s disease. Since these diseases often appear on sun-exposed skin, aesthetic results are very important. The effect of LED treatment is as good or in same data even better as in older types of PDT.
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Light emitting diodes in photodynamic therapy in non-melanoma skin cancers – own observations and literature review
Anna Erkiert-Polguj1, Adam Halbina2, Izabela Polak-Pacholczyk2, Helena Rotsztejn1,2 1
Department of Cosmetology and Aesthetic Dermatology, University of Lodz, Poland,
2
Dermed Medical Center, Lodz, Poland
Corresponding author: Anna Erkiert-Polguj, Email: [email protected], Department of Cosmetology, Faculty of Pharmacy, Medical University of Lodz, Muszynskiego 1, 90-151 Łódź, Poland
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Abstract Photodynamic therapy (PDT) employs light activation of tissue-localized photosensitizer in an oxygen-dependent process which initiates oxidative stress, inflammation and cell death. There are many indications for PDT, although the main ones are still non-melanoma skin cancers. Used light sources include coherent and non-coherent ones, but we would like to focus on the use of lightemitting diodes (LED) in PDT. We present four patients with skin lesions successfully treated with LED-based photodynamic therapy. The main advantage of that source is narrow emission spectrum that can correspond well with photosensitizers maximum absorption. Also, using LED source seems to be cheaper and simpler, and the field of irradiation is larger. The data showed good clinical and cosmetic outcome of LED-based PDT in actinic keratosis, basal cell carcinoma, Bowen's disease. Since these diseases often appear on sunexposed skin, aesthetic results are very important. The effect of LED treatment is as good or in same data even better as in older types of PDT.
Keywords: actinic keratosis, basal cell carcinoma, light-emitting diodes, photodynamic therapy Received 28 November 2014, Revised 28 April 2015, Accepted 26 June 2015
Introduction Photodynamic therapy (PDT) is based on the administration (either systemically, locally, or topically) of a non-toxic drug or dye known as a photosensitizer that selectively localizes in the target tissue, and then after incubation period employs light activation of photosensitizer in the presence of oxygen. It leads to the generation of cytotoxic species and consequently to cell death and tissue devastation. PDT therapy leads to apoptosis by mitochondrial or external way, but it may also induce necrosis (1). Although PDT therapy is mostly used for cancers, topical PDT has also been applied to a diverse range of other diseases: viral warts, acne, cutaneous T-cell lymphoma and psoriasis, acne, oral lichen planus and oral leukoplakia (2). There is a range of light sources that have been used for illumination in PDT. Light with wavelengths of 635 nm can penetrate the skin to a depth of approximately 6 mm, while a wavelength of 400- 500 nm to 1-2 mm. The therapeutic effectiveness of PDT is close to 1-3
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mm when 635 nm is used (3). Coherent (lasers) and incoherent light sources are used. The non-coherent light sources described in clinical studies on PDT include the halogen lamps (as that ones used in slide projectors), light-emitting-diode (LED) lamps and, more recently, intense pulsed light (IPL). Using incoherent light source seems to be cheaper and simpler, and field of irradiation is larger (4). Emission spectrum of LED is relatively narrow and can correspond well with photosensitizers maximum absorption and due to that fact time of irradiation can be shortened. In comparison to other incoherent light sources, using LED lets us eliminate wavelengths that are not needed to achieve therapeutic effects. Other important fact of LED sources is that they produce less heat than high-pressure lamps, are highly durable and relatively inexpensive in the long time (4,5). Clinical difficulty in photodynamic therapy is the delay between drug application and light delivery, but there are data of portable ambulatory LED sources therapy for PDT (6,7). Case report We would like to pay attention to the use of light emitting diodes in PDT. We present three patients with skin lesions treated with LED-based photodynamic therapy. Lesions were prepared by gentle superficial curettage, without local anesthesia. Aminolaevulinic acid (ALA) cream (5%) was applied under dressing (all lesion and 1cm of adjacent surrounding normal skin). After 3 h, the remaining cream was wiped off. Lesions were subsequently exposed to standard 630 nm red light emitting diode light or a total of 8 minutes 45 sec. (Aktilite; 37 J/cm2). The patients reported slight burning during therapy. The oedema and erythema lasted for several days. All subjects had the treatment repeated after 1 week and when nece ssary - 4 weeks later. The control visits were organized every three months. The patients were followed up for one year every three months and every six months next year. The Patient 1, aged 54, was diagnosed with basal cell carcinoma. Clinical diagnosis was confirmed by histopathology. (Fig. 1). Two PDT sessions led to complete lesion clearance (Fig.2).
The Patient 2, aged 91, was seen in the Clinic because of multiple actinic keratosis on his scalp (Fig.3). The treatment with one PDT session cured all lesions (Fig 4). The Patient 3, aged 55, had histopathologically confirmed Bowen's disease. (Fig 5). Complete clearance of lesion was observed after 2 PDT sessions. (Fig. 6). The Patient 4, diagnosed with squamous cell carcinoma, She was reluctant to undergo a surgery because of her age (81) (Fig.7). After two PDT sessions the lesion disappeared (Fig. 8). Discussion In clinical studies the lack of effectiveness of PDT therapy is sometimes observed, and that can be connected with lack of inactivation of lower parts of tumors, so the LED source with its larger effective penetration depth can be a better option. All these differences are related to difference in the spectra of the lamps. The researchers conclude that although PDT light sources have emissions that are visually similar, they give significantly different
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photobiological properties (5). Babilas et al. (8) displayed the efficiency of LED-based PDT on both immortalized epidermal keratinocyte cells and in vivo- patients suffering from actinic keratosis. Nonmelanoma skin cancers (NMSCs) are the most common tumors in humans. The incidence of NMSC is continuously rising (3-8% per year) and about 40-50% of patients with history of nonmelanoma skin cancers may develop further NMSCs within 5 years. Since NMSCs often arise in cosmetically sensitive areas such as the face, the goal of NMSC treatment is complete eradication of the tumor, but best cosmetic outcomes and minimal scar formation are also important. Surgical modalities – excision, Mohs micrographic surgery, and electrodesiccation with curettage – are the preferred treatments for NMSC, but cryotherapy, PDT, cytotoxic drugs are also used (9,10,11). Basal cell carcinoma (BCC) is the most common type of skin cancer in humans. For many years, the conventional therapy for BCC has been simple surgical excision, but BCC usually occurs on sun-exposed areas of the body (like face and scalp), so there is increasing interest in development of new therapeutic strategies concerning aesthetic and quality of life aspects . Photodynamic therapy as a non-invasive therapeutic modality may be considered as a valuable treatment option for BCC. The main problem of this strategy is thickness of lesion. In the research by Tehranchinia et al. (12) 66.6% of superficial BCCs (sBCCs) showed complete response to PDT included several large-sized BCCs that would have been difficult to treat by conventional methods. Nodular BCC (nBCC) and BCC N2 mm thick have worse outcomes with PDT than superficial tumors (13). Whitaker et al. (14) described positive effects of combined therapy using an Ultra Pulse CO2 and PDT using Methyl Aminolevulinate (METVIX) and the Aktilite 16 LED lamp. Firstly the vaporization of the nodular component was made and because of that the depth of penetrance of the PDT is likely to be enhanced. The only complications were mild hypopigmentation and mild discomfort during PDT.
Optimization of photodynamic therapy has led to invent a low-irradiance, potentially disposable, lightweight, organic light-emitting diode (OLED), which is an area-emitting light source (2 cm diameter), suitable for ambulatory PDT. Attili et al. (7) studied 12 patients with Bowen’s disease and superficial basal cell carcinoma < 2 cm in diameter. At the 12-month follow-up, seven of the 12 patients remained clear, with four of the nonresponders demonstrating peripheral margin failure. Pain was the other estimated aspect of the study. All 12 subjects scored pain as < 2 using the NRS scale (1-10). In contrast, a similar cohort of 50 consecutive patients treated with PDT with conventional LED source scored a median of 6 on the NRS. Cooling is often used to diminish discomfort during conventional PDT, and in that case there was no need to use it (7). Actinic keratosis (AK) is nowadays recognized as a precancerous skin disease or even very first step of squamous cell carcinoma (SCC). The international guidelines recommend an early treatment to avoid progression into squamous cell carcinoma. One of the treatment
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options is PDT that also offers an excellent cosmetic outcome (11,15,16). Most of published clinical trials concerning LED-PDT reported actinic keratosis treatment. The results are shown in Table I. There are some data that using BF-100 ALA as photosensitizer the efficiency of the treatment depends on the light source used for irradiation. PDT based on LEDs, showed highest clinical efficacies, from 85% to above 90%, when considering patients with complete clearance (17,18,19). Cryotherapy is also often used to cure AK and it seems equal or less effective than PDT, but the main advantage of using PDT in AK is superior cosmetic outcome because it is less destructive and more selective (2,20). The other aspect connected with AK is the idea of a field of cancerization. Taking this into account, PDT therapy with incoherent light source is more suitable in that case (the field of illumination is larger) (4). Babilas et al. (4) performed a prospective, randomized and controlled split-face study to asses LED-based PDT in AK. It was compared to older type of high-pressure lamp. 5-amino4-oxo-pentanoate (methylaminolevulinate, MAL) was used to PDT in 17 patients with AK lesions on the face and scalp, that were two-side symmetrically distributed. One side of treated skin was irradiated with LED lamp, and the contralateral one with high-pressure lamp. Light therapy was performed once. Six months after the treatment there was no significant difference between the infiltration and keratosis scores in both treatment regimes and patients satisfaction. Both treatment regimes are similarly painful, stinging and burning during and after irradiation was reported most frequently. Erythema and crusting appeared 2 to 4 days after treatment, lasting for 10 to 14 days. At follow-up after 3 and 6 months authors described a slight erythema, hyperpigmentation or hypopigmentation of the treated region (4). Daylight-mediated PDT seems to be simple and convenient treatment procedure. Wiegell et al. (21) compared the efficacy of LED-based PDT to daylight mediated PDT with very lowintensity artificial daylight (‘daylight’) in the treatment of multiple AKs. Although using LED were more painful, the results were more satisfactory.
In 2012 Enk and Levi (22) described red LED traffic lights as a simple alternative for PDT in actinic keratosis. The authors obtained good results and the irradiation caused no pain or other discomfort even when covering large skin areas. The low-intensity LED lamps do not generate any heat, so no cooling system was required (22). BF-200 ALA is a new nanoemulsion-based gel formulation containing 7-8% ALA (10% ALA hydrochloride) that is stabile in the aqueous formulation and shows enhanced penetration into the epidermis. In III phase clinical studies of that drug authors compared also two ways of light illumination LED one and standard broad-spectrum one. Patients irradiated with LED lamps displayed more often complete clearance after therapy and showed lower recurrence rates than those illuminated with broadband lamps (17,18,19). Morton et al. (23) compared LED-based PDT with double freeze–thaw cryotherapy in AK lesions. The study was designed as randomized and intraindividual (left-right) comparison. The clinical outcome was significantly better for LED-based PDT in 12 week, but at week
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24 there was no statistical difference. However, the cosmetic results in patients and doctors opinions were better after PDT, and also this method was less painful (23). Bowen’s disease, also known as squamous cell carcinoma in situ, is typically present on elderly patients’ skin and it very often appears on the lower legs. PDT seems to have similar clinical outcome and better cosmetic outcome than cryotherapy in this disease (11,24). Morton et al. (24) compared PDT with two different light wavelengths using xenon lamp – green and red one and at a theoretically equivalent dose green light is less effective than the red one. Kim et al (25) showed good clinical outcome of LED-based PDT in Bowen's disease with pretreatment with ablative laser that led to a shorter photosensitizer incubation time compared with the conventional PDT method. Lopez et al. (26) used LED based PDT in two session scheme to treat large Bowen's disease (defined as larger tnah 3cm). Complete response after 3 months was 90%. None of adverse effects required treatment discontinuation. In view of metastatic potential of squamous cell carcinoma, PDT is not recommended as a treatment option and comparative studies have not been performed (2). In a retrospective study (the follow up to 47 months), 35 superficial SCC (defined as SCC confined to the papillary dermis, but not in situ) treated with ALA-PDT were described. The complete primary response rate was 54% (27). PDT is well tolerated and adverse effects (if any at all) are limited to mild local pain and erythema. The adverse events of PDT were also reported to be minimal in other studies. Wang et al. (28), described that pain during PDT for BCC comparable with pain during cryotherapy. Laser or broadband light sources used for PDT do not differ in term of pain experienced (29,30), similarly there seems to be no difference between pain during LEDbased PDT or based on incoherent light sources (4,8). However, Babials et al. (31) has shown that variable pulsed light can be used for PDT and is less painful. Portable low irradiance LED devices may be used in ambulatory home PDT. They are battery-pack operated, and comparing to conventional PDT, they cause much less pain (6,7).
Also the reason for choosing PDT as a therapy option are good aesthetic results. Vinciullo et al. (32), reported that cosmetic results showed further gradual improvement over time. Conclusions Recent years have brought increasing interest in the use of LED in dermatology. The main advantage of LED-based photodynamic therapy is narrow emission spectrum that can correspond well with photosensitizers maximum absorption. Moreover, using LED source seems to be cheaper and simpler, and field of irradiation is larger. The therapy was well tolerated. The data showed good clinical and cosmetic outcome of LED-based PDT in actinic keratosis, basal cell carcinoma and Bowen's disease. Since these diseases often appear on sun-exposed skin, aesthetic results are very important. The effect of LED treatment is as good or in same data even better as in older types of PDT. That is why this therapy may be used more and more often in the future. Funding
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The study was supported by statutory research activity no: 503/3-066-01/503-01.
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Figures' Legends
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Fig.1. Patient 1. Basal cell carcinoma.
Fig. 2. Patient 1. The effect of two LED-based PDT sessions.
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Fig 3. Patient 2. Actinic keratosis before the treatment.
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Fig. 4. Patient 2. 3 months after one LED-based PDT session.
Fig.5. Patient 3. Bowen's disease on the trunk.
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Fig. 6. Patient 3. Complete disappearance of the lesion after two LED-based PDT sessions 6 weeks after the treatment.
Fig.7. Patient 4. Squamous cell carcinoma.
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Fig.8. Patient 4. Complete disappearance of the lesion after two LED-based PDT sessions - 3 months after the treatment.
Table Legend Table 1. The effectiveness of LED/PDT therapy in actinic keratosis. Study
Photosensitizer
Babilas eta al. (4)
methylaminolaevulinate
Szeimies et al. (17)
nanoemulsion-based ALA formulation, BF-200 ALA nanoemulsion-based ALA formulation, BF-200 ALA and methylaminolaevulinate nanoemulsion-based ALA formulation, BF-200 ALA
122 patients
Lis-Święty et al. (20) Wiegell et al. (21) Enk and Levi (22) low-irradiance red LED traffic lamps Morton et al. (23)
methylaminolaevulinate
18 patients
methylaminolaevulinate Aminolaevulinic acid
20 patients 15 patients
methylaminolaevulinate
119 patients
Babilas et al. (31)
methylaminolaevulinate
25 patients (120 actinic keratoses lesions)
Dirschka et al. (18)
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Dirschka et al. (19)
No of enrolled patients 17 patients
248 patients 247 patients 663 patients
Results Remission rate 78,5% (6 months after treatment) The patient and lesion complete clearance rates were 96% The patient complete clearance rates 12 weeks after the last PDT were BF-200 ALA, 84,8%, MAL- 67,5% Recurrence rates were similar for BF-200 ALA and MAL, with a tendency to lower recurrence rates for BF-200 ALA. After 3 months total healing was observed in 87% of patients Response rate 63% All improved clinically
At week 12, cured lesions 86.9%, at week 24 - 89.1% The overall lesion complete response rates at 3 months after treatment were 56,7%
ISSN: 1476-4172 (Print) 1476-4180 (Online) Journal homepage: http://www.tandfonline.com/loi/ijcl20
Light emitting diodes in photodynamic therapy in non-melanoma skin cancers – own observations and literature review Anna Erkiert-Polguj, Adam Halbina, Izabela Polak-Pacholczyk & Helena Rotsztejn To cite this article: Anna Erkiert-Polguj, Adam Halbina, Izabela Polak-Pacholczyk & Helena Rotsztejn (2016): Light emitting diodes in photodynamic therapy in non-melanoma skin cancers – own observations and literature review, Journal of Cosmetic and Laser Therapy, DOI: 10.3109/14764172.2015.1114635 To link to this article: http://dx.doi.org/10.3109/14764172.2015.1114635
Accepted author version posted online: 06 Jan 2016.
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Date: 01 February 2016, At: 01:24
Just Accepted by Journal of Cosmetic and Laser Therapy
Light emitting diodes in photodynamic therapy in non-melanoma skin cancers – own observations and literature review Anna Erkiert-Polguj, Adam Halbina, Izabela Polak-Pacholczyk, Helena Rotsztejn Doi: 10.3109/14764172.2015.1114635
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Abstract Photodynamic therapy (PDT) employs light activation of tissue-localized photosensitizer in an oxygen-dependent process which initiates oxidative stress, inflammation and cell death. There are many indications for PDT, although the main ones are still non-melanoma skin cancers. Used light sources include coherent and non-coherent ones, but we would like to focus on the use of light-emitting diodes (LED) in PDT. We present four patients with skin lesions successfully treated with LED-based photodynamic therapy. The main advantage of that source is narrow emission spectrum that can correspond well with photosensitizers maximum absorption. Also, using LED source seems to be cheaper and simpler, and the field of irradiation is larger. The data showed good clinical and cosmetic outcome of LEDbased PDT in actinic keratosis, basal cell carcinoma, Bowen’s disease. Since these diseases often appear on sun-exposed skin, aesthetic results are very important. The effect of LED treatment is as good or in same data even better as in older types of PDT.
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Light emitting diodes in photodynamic therapy in non-melanoma skin cancers – own observations and literature review
Anna Erkiert-Polguj1, Adam Halbina2, Izabela Polak-Pacholczyk2, Helena Rotsztejn1,2 1
Department of Cosmetology and Aesthetic Dermatology, University of Lodz, Poland,
2
Dermed Medical Center, Lodz, Poland
Corresponding author: Anna Erkiert-Polguj, Email: [email protected], Department of Cosmetology, Faculty of Pharmacy, Medical University of Lodz, Muszynskiego 1, 90-151 Łódź, Poland
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Abstract Photodynamic therapy (PDT) employs light activation of tissue-localized photosensitizer in an oxygen-dependent process which initiates oxidative stress, inflammation and cell death. There are many indications for PDT, although the main ones are still non-melanoma skin cancers. Used light sources include coherent and non-coherent ones, but we would like to focus on the use of lightemitting diodes (LED) in PDT. We present four patients with skin lesions successfully treated with LED-based photodynamic therapy. The main advantage of that source is narrow emission spectrum that can correspond well with photosensitizers maximum absorption. Also, using LED source seems to be cheaper and simpler, and the field of irradiation is larger. The data showed good clinical and cosmetic outcome of LED-based PDT in actinic keratosis, basal cell carcinoma, Bowen's disease. Since these diseases often appear on sunexposed skin, aesthetic results are very important. The effect of LED treatment is as good or in same data even better as in older types of PDT.
Keywords: actinic keratosis, basal cell carcinoma, light-emitting diodes, photodynamic therapy Received 28 November 2014, Revised 28 April 2015, Accepted 26 June 2015
Introduction Photodynamic therapy (PDT) is based on the administration (either systemically, locally, or topically) of a non-toxic drug or dye known as a photosensitizer that selectively localizes in the target tissue, and then after incubation period employs light activation of photosensitizer in the presence of oxygen. It leads to the generation of cytotoxic species and consequently to cell death and tissue devastation. PDT therapy leads to apoptosis by mitochondrial or external way, but it may also induce necrosis (1). Although PDT therapy is mostly used for cancers, topical PDT has also been applied to a diverse range of other diseases: viral warts, acne, cutaneous T-cell lymphoma and psoriasis, acne, oral lichen planus and oral leukoplakia (2). There is a range of light sources that have been used for illumination in PDT. Light with wavelengths of 635 nm can penetrate the skin to a depth of approximately 6 mm, while a wavelength of 400- 500 nm to 1-2 mm. The therapeutic effectiveness of PDT is close to 1-3
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mm when 635 nm is used (3). Coherent (lasers) and incoherent light sources are used. The non-coherent light sources described in clinical studies on PDT include the halogen lamps (as that ones used in slide projectors), light-emitting-diode (LED) lamps and, more recently, intense pulsed light (IPL). Using incoherent light source seems to be cheaper and simpler, and field of irradiation is larger (4). Emission spectrum of LED is relatively narrow and can correspond well with photosensitizers maximum absorption and due to that fact time of irradiation can be shortened. In comparison to other incoherent light sources, using LED lets us eliminate wavelengths that are not needed to achieve therapeutic effects. Other important fact of LED sources is that they produce less heat than high-pressure lamps, are highly durable and relatively inexpensive in the long time (4,5). Clinical difficulty in photodynamic therapy is the delay between drug application and light delivery, but there are data of portable ambulatory LED sources therapy for PDT (6,7). Case report We would like to pay attention to the use of light emitting diodes in PDT. We present three patients with skin lesions treated with LED-based photodynamic therapy. Lesions were prepared by gentle superficial curettage, without local anesthesia. Aminolaevulinic acid (ALA) cream (5%) was applied under dressing (all lesion and 1cm of adjacent surrounding normal skin). After 3 h, the remaining cream was wiped off. Lesions were subsequently exposed to standard 630 nm red light emitting diode light or a total of 8 minutes 45 sec. (Aktilite; 37 J/cm2). The patients reported slight burning during therapy. The oedema and erythema lasted for several days. All subjects had the treatment repeated after 1 week and when nece ssary - 4 weeks later. The control visits were organized every three months. The patients were followed up for one year every three months and every six months next year. The Patient 1, aged 54, was diagnosed with basal cell carcinoma. Clinical diagnosis was confirmed by histopathology. (Fig. 1). Two PDT sessions led to complete lesion clearance (Fig.2).
The Patient 2, aged 91, was seen in the Clinic because of multiple actinic keratosis on his scalp (Fig.3). The treatment with one PDT session cured all lesions (Fig 4). The Patient 3, aged 55, had histopathologically confirmed Bowen's disease. (Fig 5). Complete clearance of lesion was observed after 2 PDT sessions. (Fig. 6). The Patient 4, diagnosed with squamous cell carcinoma, She was reluctant to undergo a surgery because of her age (81) (Fig.7). After two PDT sessions the lesion disappeared (Fig. 8). Discussion In clinical studies the lack of effectiveness of PDT therapy is sometimes observed, and that can be connected with lack of inactivation of lower parts of tumors, so the LED source with its larger effective penetration depth can be a better option. All these differences are related to difference in the spectra of the lamps. The researchers conclude that although PDT light sources have emissions that are visually similar, they give significantly different
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photobiological properties (5). Babilas et al. (8) displayed the efficiency of LED-based PDT on both immortalized epidermal keratinocyte cells and in vivo- patients suffering from actinic keratosis. Nonmelanoma skin cancers (NMSCs) are the most common tumors in humans. The incidence of NMSC is continuously rising (3-8% per year) and about 40-50% of patients with history of nonmelanoma skin cancers may develop further NMSCs within 5 years. Since NMSCs often arise in cosmetically sensitive areas such as the face, the goal of NMSC treatment is complete eradication of the tumor, but best cosmetic outcomes and minimal scar formation are also important. Surgical modalities – excision, Mohs micrographic surgery, and electrodesiccation with curettage – are the preferred treatments for NMSC, but cryotherapy, PDT, cytotoxic drugs are also used (9,10,11). Basal cell carcinoma (BCC) is the most common type of skin cancer in humans. For many years, the conventional therapy for BCC has been simple surgical excision, but BCC usually occurs on sun-exposed areas of the body (like face and scalp), so there is increasing interest in development of new therapeutic strategies concerning aesthetic and quality of life aspects . Photodynamic therapy as a non-invasive therapeutic modality may be considered as a valuable treatment option for BCC. The main problem of this strategy is thickness of lesion. In the research by Tehranchinia et al. (12) 66.6% of superficial BCCs (sBCCs) showed complete response to PDT included several large-sized BCCs that would have been difficult to treat by conventional methods. Nodular BCC (nBCC) and BCC N2 mm thick have worse outcomes with PDT than superficial tumors (13). Whitaker et al. (14) described positive effects of combined therapy using an Ultra Pulse CO2 and PDT using Methyl Aminolevulinate (METVIX) and the Aktilite 16 LED lamp. Firstly the vaporization of the nodular component was made and because of that the depth of penetrance of the PDT is likely to be enhanced. The only complications were mild hypopigmentation and mild discomfort during PDT.
Optimization of photodynamic therapy has led to invent a low-irradiance, potentially disposable, lightweight, organic light-emitting diode (OLED), which is an area-emitting light source (2 cm diameter), suitable for ambulatory PDT. Attili et al. (7) studied 12 patients with Bowen’s disease and superficial basal cell carcinoma < 2 cm in diameter. At the 12-month follow-up, seven of the 12 patients remained clear, with four of the nonresponders demonstrating peripheral margin failure. Pain was the other estimated aspect of the study. All 12 subjects scored pain as < 2 using the NRS scale (1-10). In contrast, a similar cohort of 50 consecutive patients treated with PDT with conventional LED source scored a median of 6 on the NRS. Cooling is often used to diminish discomfort during conventional PDT, and in that case there was no need to use it (7). Actinic keratosis (AK) is nowadays recognized as a precancerous skin disease or even very first step of squamous cell carcinoma (SCC). The international guidelines recommend an early treatment to avoid progression into squamous cell carcinoma. One of the treatment
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options is PDT that also offers an excellent cosmetic outcome (11,15,16). Most of published clinical trials concerning LED-PDT reported actinic keratosis treatment. The results are shown in Table I. There are some data that using BF-100 ALA as photosensitizer the efficiency of the treatment depends on the light source used for irradiation. PDT based on LEDs, showed highest clinical efficacies, from 85% to above 90%, when considering patients with complete clearance (17,18,19). Cryotherapy is also often used to cure AK and it seems equal or less effective than PDT, but the main advantage of using PDT in AK is superior cosmetic outcome because it is less destructive and more selective (2,20). The other aspect connected with AK is the idea of a field of cancerization. Taking this into account, PDT therapy with incoherent light source is more suitable in that case (the field of illumination is larger) (4). Babilas et al. (4) performed a prospective, randomized and controlled split-face study to asses LED-based PDT in AK. It was compared to older type of high-pressure lamp. 5-amino4-oxo-pentanoate (methylaminolevulinate, MAL) was used to PDT in 17 patients with AK lesions on the face and scalp, that were two-side symmetrically distributed. One side of treated skin was irradiated with LED lamp, and the contralateral one with high-pressure lamp. Light therapy was performed once. Six months after the treatment there was no significant difference between the infiltration and keratosis scores in both treatment regimes and patients satisfaction. Both treatment regimes are similarly painful, stinging and burning during and after irradiation was reported most frequently. Erythema and crusting appeared 2 to 4 days after treatment, lasting for 10 to 14 days. At follow-up after 3 and 6 months authors described a slight erythema, hyperpigmentation or hypopigmentation of the treated region (4). Daylight-mediated PDT seems to be simple and convenient treatment procedure. Wiegell et al. (21) compared the efficacy of LED-based PDT to daylight mediated PDT with very lowintensity artificial daylight (‘daylight’) in the treatment of multiple AKs. Although using LED were more painful, the results were more satisfactory.
In 2012 Enk and Levi (22) described red LED traffic lights as a simple alternative for PDT in actinic keratosis. The authors obtained good results and the irradiation caused no pain or other discomfort even when covering large skin areas. The low-intensity LED lamps do not generate any heat, so no cooling system was required (22). BF-200 ALA is a new nanoemulsion-based gel formulation containing 7-8% ALA (10% ALA hydrochloride) that is stabile in the aqueous formulation and shows enhanced penetration into the epidermis. In III phase clinical studies of that drug authors compared also two ways of light illumination LED one and standard broad-spectrum one. Patients irradiated with LED lamps displayed more often complete clearance after therapy and showed lower recurrence rates than those illuminated with broadband lamps (17,18,19). Morton et al. (23) compared LED-based PDT with double freeze–thaw cryotherapy in AK lesions. The study was designed as randomized and intraindividual (left-right) comparison. The clinical outcome was significantly better for LED-based PDT in 12 week, but at week
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24 there was no statistical difference. However, the cosmetic results in patients and doctors opinions were better after PDT, and also this method was less painful (23). Bowen’s disease, also known as squamous cell carcinoma in situ, is typically present on elderly patients’ skin and it very often appears on the lower legs. PDT seems to have similar clinical outcome and better cosmetic outcome than cryotherapy in this disease (11,24). Morton et al. (24) compared PDT with two different light wavelengths using xenon lamp – green and red one and at a theoretically equivalent dose green light is less effective than the red one. Kim et al (25) showed good clinical outcome of LED-based PDT in Bowen's disease with pretreatment with ablative laser that led to a shorter photosensitizer incubation time compared with the conventional PDT method. Lopez et al. (26) used LED based PDT in two session scheme to treat large Bowen's disease (defined as larger tnah 3cm). Complete response after 3 months was 90%. None of adverse effects required treatment discontinuation. In view of metastatic potential of squamous cell carcinoma, PDT is not recommended as a treatment option and comparative studies have not been performed (2). In a retrospective study (the follow up to 47 months), 35 superficial SCC (defined as SCC confined to the papillary dermis, but not in situ) treated with ALA-PDT were described. The complete primary response rate was 54% (27). PDT is well tolerated and adverse effects (if any at all) are limited to mild local pain and erythema. The adverse events of PDT were also reported to be minimal in other studies. Wang et al. (28), described that pain during PDT for BCC comparable with pain during cryotherapy. Laser or broadband light sources used for PDT do not differ in term of pain experienced (29,30), similarly there seems to be no difference between pain during LEDbased PDT or based on incoherent light sources (4,8). However, Babials et al. (31) has shown that variable pulsed light can be used for PDT and is less painful. Portable low irradiance LED devices may be used in ambulatory home PDT. They are battery-pack operated, and comparing to conventional PDT, they cause much less pain (6,7).
Also the reason for choosing PDT as a therapy option are good aesthetic results. Vinciullo et al. (32), reported that cosmetic results showed further gradual improvement over time. Conclusions Recent years have brought increasing interest in the use of LED in dermatology. The main advantage of LED-based photodynamic therapy is narrow emission spectrum that can correspond well with photosensitizers maximum absorption. Moreover, using LED source seems to be cheaper and simpler, and field of irradiation is larger. The therapy was well tolerated. The data showed good clinical and cosmetic outcome of LED-based PDT in actinic keratosis, basal cell carcinoma and Bowen's disease. Since these diseases often appear on sun-exposed skin, aesthetic results are very important. The effect of LED treatment is as good or in same data even better as in older types of PDT. That is why this therapy may be used more and more often in the future. Funding
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The study was supported by statutory research activity no: 503/3-066-01/503-01.
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Figures' Legends
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Fig.1. Patient 1. Basal cell carcinoma.
Fig. 2. Patient 1. The effect of two LED-based PDT sessions.
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Fig 3. Patient 2. Actinic keratosis before the treatment.
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Fig. 4. Patient 2. 3 months after one LED-based PDT session.
Fig.5. Patient 3. Bowen's disease on the trunk.
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Fig. 6. Patient 3. Complete disappearance of the lesion after two LED-based PDT sessions 6 weeks after the treatment.
Fig.7. Patient 4. Squamous cell carcinoma.
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Fig.8. Patient 4. Complete disappearance of the lesion after two LED-based PDT sessions - 3 months after the treatment.
Table Legend Table 1. The effectiveness of LED/PDT therapy in actinic keratosis. Study
Photosensitizer
Babilas eta al. (4)
methylaminolaevulinate
Szeimies et al. (17)
nanoemulsion-based ALA formulation, BF-200 ALA nanoemulsion-based ALA formulation, BF-200 ALA and methylaminolaevulinate nanoemulsion-based ALA formulation, BF-200 ALA
122 patients
Lis-Święty et al. (20) Wiegell et al. (21) Enk and Levi (22) low-irradiance red LED traffic lamps Morton et al. (23)
methylaminolaevulinate
18 patients
methylaminolaevulinate Aminolaevulinic acid
20 patients 15 patients
methylaminolaevulinate
119 patients
Babilas et al. (31)
methylaminolaevulinate
25 patients (120 actinic keratoses lesions)
Dirschka et al. (18)
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Dirschka et al. (19)
No of enrolled patients 17 patients
248 patients 247 patients 663 patients
Results Remission rate 78,5% (6 months after treatment) The patient and lesion complete clearance rates were 96% The patient complete clearance rates 12 weeks after the last PDT were BF-200 ALA, 84,8%, MAL- 67,5% Recurrence rates were similar for BF-200 ALA and MAL, with a tendency to lower recurrence rates for BF-200 ALA. After 3 months total healing was observed in 87% of patients Response rate 63% All improved clinically
At week 12, cured lesions 86.9%, at week 24 - 89.1% The overall lesion complete response rates at 3 months after treatment were 56,7%
