Photodynamic therapy in dermatology: basic principles

Abstracts

A terapia fotodinâmica envolve a administração de uma droga fotossensibilizante e sua ativação subsequente pela luz de comprimento de onda correspondente ao espectro de absorção do fotossensibilizador. Atualmente, a terapia fotodinâmica tópica é aprovada para o tratamento de condições oncológicas cutâneas como queratoses actínicas, doença de Bowen e carcinoma basocelular superficial em diversos países do mundo. Estudos multicêntricos controlados e randomizados demonstram a alta eficácia e resultado cosmético final superior dessa modalidade terapêutica em relação aos tratamentos convencionais. Para condições cutâneas não oncológicas, como acne vulgar, verrugas virais e esclerodermia localizada, há também relatos e série de casos confirmando o potencial terapêutico da terapia fotodinâmica. O desenvolvimento de fotossensibilizantes tópicos, ácido 5-aminolevulínico (ALA) ou seu metiléster (MAL), frente aos derivados da hematoporfirina de aplicação sistêmica, permitiu um grande avanço na popularidade da TFD na dermatologia, uma vez que tanto ALA quanto MAL tópicos não induzem mais fotossensibilidade generalizada prolongada. A produção de intermediários reativos de oxigênio, como oxigênio singlet, depende da concentração, da localização do fotossensibilizante no tecido alvo, assim como da dose de luz utilizada. Tanto as lâmpadas de amplo espectro quanto os LEDs (do inglês light emitting diodes) constituem fontes de luz adequadas para que os efeitos citotóxicos da terapia fotodinâmica resultem na destruição do tumor ou seus efeitos imunomodulatórios atuem melhorando as condições inflamatórias cutâneas.

Carcinoma basocelular; Carcinoma in situ; Fotoquimioterapia

CONTINUING MEDICAL EDUCATION

Photodynamic therapy in dermatology: basic principles

Luís Torezan^I; Ane Beatriz Mautari Niwa^II; Cyro Festa Neto^III

^IMaster in dermatology, Medical School, Universidade de São Paulo (FMUSP), Ph.D. studies under course, Department of Dermatology, Medical School, Universidade de São Paulo (FMUSP) – São Paulo (SP), Brazil

^IIDermatologist, Graduate studies under course, Department of Dermatology, Medical School, Universidade de São Paulo (FMUSP) – São Paulo (SP), Brazil

^IIIPh.D., Professor, Medical School, Universidade de São Paulo (FMUSP) – São Paulo (SP), Brazil. Faculty Professor, Medical School, Universidade de São Paulo (FMUSP) – São Paulo (SP), Brazil

^{Mailing Address}

ABSTRACT

Photodynamic therapy involves the administration of a photosensitizing drug and its subsequent activation by light at wavelengths matching the absorption spectrum of the photosensitizer. Currently, topical photodynamic therapy has received approval for the treatment of cutaneous oncologic conditions such as actinic keratoses, Bowen’s disease and superficial basal cell carcinoma in many countries in the world. Multicenter randomized controlled studies have demonstrated high efficacy and superior cosmetic outcome over standard therapies. For many non-oncologic dermatological diseases such as acne vulgaris, viral warts and localized scleroderma, case reports and small series have confirmed the potential of photodynamic therapy. After the development of topical photosensitizers 5-aminolevulinic acid (ALA) or its methyl ester (MAL), photodynamic therapy has gained worldwide popularity in dermatology, as these drugs do not induce prolonged phototoxicity as the systemic photosensitizing hematoporphyrin derivatives do. The production of reactive oxygen intermediates such as singlet oxygen depends on the concentration and localization of the photosensitizer in the diseased tissue as well as the applied light dose. Either incoherent lamps or LED arrays are suitable for the cytotoxic effects resulting in tumor destruction or immunomodulatory effects improving inflammatory condition.

Keywords: Carcinoma, basal cell; Carcinoma in situ; Photochemotherapy

INTRODUCTION

Photodynamic therapy (PDT) is a therapeutic modality that has been used in the treatment of many malignant tumors in different areas of medicine.

In dermatology, PDT is used to treat non-melanocytic skin cancer treatment (NMSC) and other inflammatory and proliferative non-neoplastic diseases such as psoriasis, Darier disease, sarcoidosis and lipoidic necrobiosis. In recent decades, PDT progressed from experimental therapeutic resources for the first option of treatment of lesions as actinic keratosis (AK) and other extensive superficial lesions such as superficial basal cell carcinoma (BCC) and Bowen disease (BD) ^1-3.

To present, we can see a huge growth of PDT and its applications. It is both a fascinating and a controversial area because it combines many drugs, protocols, light sources, new indications that may confuse the medical professional that is starting an experience with PDT. Thus, the understanding of basic principles as well as the knowledge about agents, light sources and action mechanisms becomes imperative for the appropriate use of the techniques towards the best results possible.

BACKGROUND

PDT started in the XX century in Munich when Oscar Raab, a medical student guided by Professor Herman Von Tappeiner observed the effects resulting from the photosensitization in paramecium 4. The interest of the study was to identify the process in which quinine was effective against malaria, whereas other agents such as acridine (coaltar derivate) were toxic against protozoa in vitro, but not in vivo. Raab observed that paramecium died between 60 to 100 minutes after acridine, in the concentration 1:20,000, had been added as a medium. In another experiment, paramecium survived for 800 to 1,000 minutes with the same concentration as acridine. The only difference was the occurrence of a major storm, leading to adverse conditions of environmental luminosity and then researchers started to wonder whether the light had influenced in the results. The continuation of the studies confirmed that acridine and light increased the toxicity of paramecium, whereas isolated acridine,

isolated light or acridine exposed to light and later added to the medium were atoxic ^4-8.

In 1960, a compound purified from hematoporphyrin was synthesized and named HpD. In the 1970s and 80s, studies were carried out with the use of a HpD purified derivate known as sodium porphymer, to treat bladder, lung, esophagus, stomach, skin and gynecological tumors ^9-12. In the beginning of the 1990’s in Canada, sodium porphymer was the first drug approved by therapeutic use 9.

Prolonged photosensitivity with the use of systemic drugs and high indexes of cure obtained with other more practical methods reduced the interest in this dermatology method. In this sense, new drugs, known as second generation, were developed and contributed to the most recent advances in PDT in dermatology.

In 1990, Kennedy et al. revolutionized PDT by using a topical substance: acid 5-delta aminolevulinic (5-ALA). It is a porphyrin precursor (protoporphyrin IX or PPIX) which is synthesized inside the cells by biosynthesis of heme group ¹³. PPIX is considered a powerful photosensitizing agent which is easily photoinactivated ^13,14. At the end of the 1990’s, a new drug derived from 5-ALA was synthesized, methyl aminolevulinate. It is an esterified compound of 5-ALA that may have lipophilic property, which has the advantage of greater penetration and specificity in tissue tumor. The action mechanism seems to be the same in both drugs.

Thus, PDT is a topical drug capable of inducing localized and selective photosensitivity in the cutaneous area to be treated such as superficial BCC, superficial SCC (in situ) and AK ^1,13,14.

Photosensitizing Agents

Topical Agents

5- ALA and MAL

ALA is a hydrophilic agent that is captured by the cells especially by active transportation such as NA+/CL- dependent of beta amino acids such as glycine and gamma aminobutyric acid (GABA) as carriers ¹⁵. These systems require energy, dependent of pH and temperature, are slow and saturable and are a bit more accelerated in tumor cells ¹⁵. MAL is a lipophilic molecule that is captured by active transportation mechanisms especially those dependent of non-polar amino acids such as alanine, methionine, tryptophan and glycine. However, MAL is also captured by passive mechanisms of transmembrane diffusion ^15-16. This mechanism does not require energy and it is not saturable, being effective in normal cells, even more in neoplastic cells. This plurarity of factors might explain the greater penetration of MAL in relation to ALA, especially in malignant cells.

ALA is the first intermediate in the biosynthesis route of Heme group, being synthesized from glycine and succinyl – Coa, inside the mitochondria (Figure 1). This region is catalyzed by enzyme ALA-synthetase. In the cytoplasm of cell, two ALA molecules form porphobilinogenium (PBG) and 4 cells of PBG form uroporphyrinogenium III. The latter is converted into coproporphyrinogenium III and again inside the mitochondria, in protoporphyrinogenium IX, which is converted into PpIX, by the action of protoporphyrinogenium oxidase ^16-18.

PpIX is a porphyrin intermediate with photodynamic activity and when activated by blue light, it emits intense red fluorescence.

The normal synthesis of ALA inside the cell is controlled by ALA synthetase enzyme which in turn is inhibited by accumulation of heme groups (negative feedback). Without excessive exogenous ALA applied topically, there is quick passage through the abnormal epidermis and later conversion into PpIX inside the mitochondria. Once the conversion of PpIX into heme is a slow reaction, cells tend to accumulate great concentrations of PpIX. Excessive accumulation of PpIX inside the mitochondria induces to diffusion to the endoplasmatic reticulum and cell membrane, both final targets to cell damage induced by PDT.

When MAL is applied topically, the molecule is quickly dimethylated to ALA and suffers the same process of metabolization, as exposed above 15.

PPIX has many peaks of light absorption. The main band of Soret in 405 nm, corresponding to blue light. Other smaller peaks are also important and named Q bands. There are peaks in 510, 545, 580, 630, 670 and 700 nm (Graph 1). Even though the peaks of Q bands are 10 to 40x smaller than the peak in 405 nm, many studies in PDT are conducted by using light source in red light spectrum between 620 and 635 nm, which provides greater penetration into the tissue, optimizing PDT to deeper lesions. However, green and blue sources are also employed in PDT for superficial lesions and with similar results ^15-21.

Some factors interfere with the penetration of ALA on the skin: concentration, type of vehicle used in the preparation, time of application and use of adjuvant agents that favor the accumulation of PpIX in tumor cells. In clinical studies, concentrations of ALA vary between 5 and 20% ^15,16,20,22. The best therapeutic results were obtained with concentrations between 10 and 20% ^15-23. Currently, they use ALA 20% in water/ oil emulsion and hydro-alcoholic solution (commercially available as tube preparation, and ALA powder is separated from the solution for topical use) ²¹. MAL is only available in the form of cream containing archis oil, glyceryl and water at 16% concentration, commercially available in the form of 2g tubes, ready for topical use ^24-27.

Concerning time of application over the lesion, there is great variation of 3 to 20 hours ^{13,14,19,28-29}. Some recent studies use ALA without occlusion with time of application of 15 to 60 minutes for photorejuvenation and acne ²¹. The current protocols approved for topical ALA use in the treatment of AK are prolonged application between 14-18 hours ^21,27. In the case of MAL, the application time is 3 hours under occlusion ²⁷.

The use of adjuvant agents in ALA formulations may increase, direct or indirectly, to the formation of PpIX in tumor cells. The addition of agents that inhibit the action of ironquelatase enzymes or increase the penetration of ALA in the tissue, such as the case with desferroxamine, ethylenediamine tetracetic acid (EDTA) and dimethyl sulfoxide (DMSO) are examples of additives that maximize PDT ²⁰. Other techniques that may enhance the concentration of PpIX may increase the absorption of ALA, such as in the case of iontophoresis ³¹.

ACTION MECHANISM

The concept of PDT is the induction to cytotoxicity of proliferative cells using a light source. For it to happen, three components are required: photosensitizing agent, light and oxygen ^9,10.

In general, the technique consists of two steps. In the first stage, the photosensitizing agent is accumulated in the tumor cells after topical or systemic administration. In the second stage, the photosensitized tumor is exposed to wave length light that coincides with the spectrum of absorption of the photosensitizing agent. ^{9,10,15,16,21,30}

During the PDT, the photosensitizing agent linked to the tumor is activated in the presence of light. This activation leads from the stage of rest to the stage of activation, named singlet, of short half-life. In this stage, molecules may resume their state at rest, issuing energy in the form of fluorescence by releasing photons or progressing in the chemical reaction chains, up to reaching the triplet of longer half-life. Molecules in the triplet status transferred its energy directly to intracellular oxygen, forming the singlet oxygen (¹O₂), highly reactive, of short half-life and responsible for cell death ^9,10.

As a consequence of ¹O₂ action, tumor cells start to present integrity fails of the membrane, which leads to abnormalities in the permeability and function of transportation between the intra and extracellular mediums. Abnormalities in the membrane of the nucleus, mitochondria, lisosome and endoplasmatic reticulum may also occur ^15,16,32. Studies using fluorescence microscopy suggested that mitochondrial phototoxicity is the main cause of cell death induced by PDT ^15,32. Despite the exact location of the cytotoxic effect, the consequence is loss of cell integrity, leading to release of inflammatory factors and activation of complement cascade ¹⁶.

During PDT, selectivity of treatment depends on the area exposed to light and the preferential accumulation of photosensitizing agent in tumor cells in relation to normal tissue. Even though the accumulation is preferential it is not well understood, but some factors are appointed as being responsible ^9,16,27. Tumor cell membrane permeability is abnormal. This fact may be confirmed by the quick passage of dye, such as Evans blue and Congo red, from inside the capillaries to the tumor stroma ^9,10. The collagen fibers that integrate the tumor are immature and the process of scarring is recent. These immature fibers have greater capacity of porphyrin binding, creating a site of retention and accumulation of photosensitizing agent 9. Other factors that also collaborate are poorly developed lymphatic network, ligation of porphyrins to surface receptors of low density lipoproteins in tumor cells, presence of macrophages and lower intracellular pH. ^9,10

Light Sources

Three different groups of light source may be characterized by PDT: broad spectrum bulbs, diode bulbs and lasers. The action of these devices depends primarily on the emission spectrum, irradiance, light spatial distribution and device power ^9,10,15,16.

High pressure or fluorescent broad spectrum light comprises almost all visible light and beginning of infrared, sparing almost completely UV radiation. Metallic halogen bulbs are broadly used because they are cheap and have high irradiance, which maintains constant light exposure and promote not very long PDT. They can be used as source of slide projectors (white light) or equipped with optical filters that promote the selection of light bands. The most used fluorescent bulb operates with light blue range in 407 nm (Soret band), which is enough to promote photodynamic activation of 5-ALA (Blu- U®, Dusa Pharmaceuticals, USA). ^33-35

LEDs (or light emitting diodes) are devices comprised of solid semi-conductors linked among them and that generate light. They provide reliable light source and high power light in narrow bands (between 20-50 nm) and may be distributed in panels to promote the lighting of a broad and homogenous surface. This last item is very important because irregular light distribution may fail to address parts of the more extensive superficial tumor. They are of easy use and have long half-life ¹⁵.

Irradiance and uniformity of irradiation should be constantly checked during PDT. Irradiance is used in PDT range from 50 to 150 mW/cm².Very low irradiances time of exposure to light source may be very long, whereas in very high irradiances there may be an additive thermal effect in PDT. During tumor radiation there was a process known as photosensitizing drugs (or photobleaching), that is, as the tumor is destroyed by photodynamic activation there is parallel inactivation of the agent by light absorption ^9,10.

Contrary to lamps, lasers provide light in specific wave length that may be compatible with the main spectrum of photosensitizing agent absorption, in addition to light beam that is quite homogenous. Many lasers have been used in PDT as argon dye laser, Nd: YAG, copper vapor dye, gold vapor, and diode laser ^15,16. The use enables performance of faster PDT, because it has high flow of monochromatic light and corresponds to the peak of agent absorption. However, expensive devices are not portable, demand more technical support and enlighten small skin areas.

When we assess the main publications of PDT with lasers or non-coherent light sources (LEDs and halogen bulbs), it is important to reinforce that the flow can only be compared when considering the irradiance of the devices. For example, broad spectrum halogen lamps issue photons in very short or very long wavelengths that are not necessary for the activation of a photosensitizing agent, resulting in dispersed photons and leading to overestimate of the effective flowability when compared to lasers ^9,10,16.

CLINICAL ONCOLOGY APPLICATIONS IN DERMATOLOGY:

5-ALA and MAL

Methyl aminolevulinate (Metvix®, Galderma, France) is approved in countries in European Community, Latin America, Australia, New Zealand and the United States and 5-ALA (Levulan Kerastisck®, Dusa Pharmaceuticals, USA) in the United States and Canada as topical precursors of photosensitizing agents for PDT. The correct choice of light source is of extreme importance. Even though blue light enables photodynamic activation and enough penetration for treatment of superficial AK, red light provides greater penetration into the tissue, which is more effective in thicker lesions such as BCC. The treatment protocol with 5-ALA is made with fluorescent blue light source 417 nm in the total dose of 10 J/cm² (Blu-U, Dusa Pharmaceuticals, USA), whereas with MAL the light source is 635 nm LED in the total dose of 37 J/cm². ^21,27

The studies published on PDT to treat AK involve both ALA and MAL. All evidence has shown that PDT is highly effective. The complete response of lesions with MAL, after 3-month follow-up, showed 90% cure and about 89% to 91% for ALA in the same period of follow-up ^{24,25,33,34,36,37} In a recent publication, Tarstedt et al. observed that only one session of MAL-PDT repeated 3 months later if necessary, is equally effective and the cure rate is 92%, similar to the initial protocol ³⁷. Thus, to treat KA with MAL, we advocate only one session and, if necessary, a new sessions 3 months later, in case of partial response. It is important to highlight that we should always prepare the lesions before MAL application, that is, to perform slight curettage of lesions to remove the most superficial layers of keratin.

The studies that compared PDT with cryosurgery and 5-fluoracyl showed efficacy at least equal or greater than PDT. However, the final cosmetic outcomes obtained with PDT have always been superior in all publications. Studies have shown excellent cosmetic results between 91% and 98% in treated patients. ^21,27,28,39

Concerning Bowen disease (BD), studies carried out with ALA (in general ALA 20% in cream formulations with variable light sources) have shown cure rates of 88% to 100% ^27,38-40. In the largest multicenter study carried out by Morton et al., the initial cure rate was 93%. After 24 months, recurrence was 18%. In the same study, in which the authors compared cryosurgery and 5-fluoracyl, recurrence in the later was 23% and 21%, respectively ⁴⁰. However, the final cosmetic outcome, as well as the preference for the method, was much greater for PDT when compared to the others ⁴¹ (Figures 2 and 3).

PDT is also considered a non-invasive modality for superficial BBC, with many studies that support its use ^27,42-44. In a recent multicenter study carried out by Basset-Seguin et al. the cure rate was 97% after 3-month follow-up; in a follow-up greater than 5 years, the observed recurrence rate was 22%. The study was compared with cryosurgery, which showed initial cure rate of 95% and recurrence of 20% after 5 years, without statistically significant difference between the methods. A relevant fact was the final cosmetic aspect with great advantage to PDT, compared to the postoperative discomfort and scarring disorders frequently observed in cryosurgery 43. In patients with "difficult to treat" superficial BCC and/or nodular tumors (extensive recurrent lesions, difficult to heal sites or patients with systemic diseases that hinder treatment) recurrence rates of 15% to 31% were observed after 36 months of follow-up ^45,46. To treat BCC with MAL, the treatment protocol is 2 sessions within 7-day intervals.

Even though recurrence rates are higher, PDT may be considered a good option in view of situations in which surgery may be avoided 27. Smaller studies with ALA and PDT were carried out with superficial BCC, showing efficacy of 90% to 100% (ALA 20% and halogen lamps) ^{19,20,22,23,28,29,42,47,48} (Figure 4).

The use of topical drugs in PDT for nodular BCC is critical, because both light ad drug penetration into the tissue end up limiting the results. MAL presents greater penetration in nodular BCC than ALA, owing to its greater lipophilic capability and smaller pole charge. In MAL protocol for nodular BCC, curettage of upper part of the tumor is advocated, even if there is bleeding, immediately before application of the product ²⁷. In most times, we can control bleeding by compressing the site.

Many studies with PDT present cure rates of 50% to 94% with ALA or MAL. Rhodes et al., 2007, showed efficacy of MAL-PDT with nodular BCC and compared it to conventional surgery. In the 3 initial months, the cure rate was 91% to PDT and 98% to surgery. After 5 years, there was recurrence of 14% in the PDT group and 4% in the surgically treated group. It is interesting to emphasize that it was a randomized prospective study with histopathology analysis. After 5 years, the final cosmetic result was assessed as good or excellent in 87% of the group treated with PDT and 54% with surgery 49. Horn et al. and Vinciullo et al. assessed the effects of MAL-PDT in BCC of difficult treatment and high risk, and even so, they had good results after 3 months follow-up: 94% and 87% of cure rate. After follow-up of 48 and 60 months, recurrence rate was of 18% and 30% 45, 46. The use of ALA for nodular BCC showed responses that ranged from 50% to 92% ^{22,23,28,29,44,47,50,51}. The lowest response rate may be due to lack of previous preparation of the lesion, as well as the differences in used light sources. Moreover, probably, the lower penetration of ALA in the tissue is due to broad response margin ^44,49-51.

It is known that MAL may penetrate up to 2mm into the tissue. Thus, thinner nodular BCC out of the risk area present better cure rates. Thus, MAL-PDT should be considered a therapeutic option for these lesions, providing high cure rate and excellent cosmetic outcome ^26,27,52.

NON-ONCOLOGY INDICATIONS OF PDT IN DERMATOLOGY

Therapeutic protocols of PDT in inflammatory cutaneous conditions differ significantly from those used in tumor treatment. Whereas in treating tumors cellular destruction by PDT is the main objective, in inflammatory dermatosis, PDT presents a likely role in the modulation of cellular function. Lower doses of light and photosensitizing drugs are used in those inflammatory skin diseases. However, multiple sessions are required to reach the therapeutic effect with few adverse events. It is important to point out that for non-oncology indications in dermatology there are few controlled and randomized clinical trials, but there are many publications in the medical literature that demonstrate that PDT is a valuable and safe therapeutic option in treating acne vulgaris, psoriasis, viral warts and localized scleroderma ⁵³.

ACNE VULGARIS

The possible action mechanisms of PDT in acne are photodestruction of P. acnes, reduction of sebaceous production, and reduction of follicular hyperkeratosis ^54-56.

Hongcharu et al. ⁵⁶ carried out a prospective study in which they showed the effect of ALA-PDT in 22 patients with acne on the back, dividing the treated area into ALA-PDT, only ALA, only light and no treatment. Eleven patients were treated with one single session and eleven were treated 4 times. They used ALA (20%) under occlusion for 3 hours and then the area was irradiated with red light (550-700 nm, 150 J cm^-2). There was significant reduction (p < 0.05) of inflammatory acne 10 weeks after the session and only 20 weeks after multiple treatment with PDT. Histopathology exam showed acute cytotoxic damage of sebaceous glands. The adverse events founds were pain, erythema, edema, transient hyperpigmentation and in some cases there were purpura and acute acneiform eruptions.

Itoh et al. ⁵⁷ assessed 23 patients with difficult to treat facial acne submitted to 1 session of ALA-PDT. ALA 20% in emulsion was applied for 4 hours and then the area was irradiated with halogen lamp (600-700 nm, 17 mW cm^-2, 13 J cm^-2). The results were apparent improvement and reduction of the onset of new acne lesions for more than 6 months after treatment with PDT.

Hörfelt et al. ⁵⁸ treated 30 patients with moderate facial acne with 2 sessions of MAL-PDT in a randomized blind controlled trial. Each hemiface received MAL or placebo under occlusion for 3 hours and then the areas were irradiated with non-coherent red light (635 nm, 37 J cm²). There was significant reduction (p < 0.05) of inflammatory lesions after MAL-PDT compared to the placebo group, with 63% improvement after 6 weeks and 54% after 12 weeks.

Wiegell et al.⁵⁹ carried out a comparative study between ALA-PDT and MAL-PDT in 15 patients with moderate facial acne. Each affected hemiface received randomly ALA 20% 2g cream and MAL cream under occlusion for 3 hours. Irradiation was made with non-coherent red light (635 nm, 34 mW/cm², 37 J cm²). The observed result was improvement in 59% of the lesions, without any statistical difference between the two treatments. ALA-PDT presented more prolonged and intense adverse effects after treatment.

Studies have demonstrated the therapeutic beneficial effects of PDT in inflammatory acne with the advantage of being a systemic treatment, with better compliance to treatment as opposed to prolonged courses of antibiotics, which present increased risk of bacterial resistance. Moreover, PDT may be remembered as a therapeutic option in case of contraindication to systemic isotretinoin. The main limitations of this therapeutic modality include standardization of treatment parameters (time of incubation, type of light, number of sessions, maintenance), high cost and especially pain management to optimize the results and minimize adverse events.

VIRAL WARTS

Vulgaris warts of the hands and feet, flat warts and genital warts (condyloma acuminatum) are common skin diseases induced by human papilloma virus (HPV). In clinical practice, there is frequent high rate of recurrence after surgical removal or use of cytotoxic drugs. In the literature, there are studies showing good results of PDT in treating recalcitrating warts 60-64. The mechanism of action involves the accumulation of PpIX induced by ALA in epidermal cells that are quickly proliferating 65, 66 and the viracidal properties of ALA-PDT ⁶⁷.

VULGAR WARTS

The first studies carried out by Kennedy et al. ⁶⁸, and Amman et al. ⁶⁹ did not show success with the treatment of vulgar warts with ALA-PDT. The likely cause of the therapeutic failure was absence of previous preparation of the lesions. Thus, prominent hyperkeratosis of warts prevented efficient skin penetration of ALA. Smetana et al ⁶⁷ tried to increase the effectiveness of treatment by using EDTA (2%) and DMSO (2%) to increase penetration of ALA. A renal transplanted patient that presented disseminated vulgar warts was successfully treated and had no recurrence in 2-year follow-up.

Stender et al. ⁶¹ carried out a pilot study in which they compared visible light sources, blue light and red light with ALA-PDT and demonstrated that visible light was more effective, followed by red light and blue light. Complete response rates were 73%, 42% and 28%, respectively (slide projector with different wave lengths, total dose 40 J/cm², total period of incubation of 5 hours). Later, the same group published a randomized double blind study with 45 patients comparing the use of ALA-PDT and placebo in recalcitrating warts of the hands and feet ⁶². Complete response rate was 56% (Waldmann PDT I200, 590-700 nm, total dose 70 J/cm², incubation period of 4 hours), which was statistically superior to placebo.

In 2001, Fabbrocini et al. 63 showed complete response rate of 75% (Tungsten lamp 400-700 nm; total dose 50 J/cm², incubation period of 5 hours). The use of keratolytic and previous superficial curettage can be used to justify the favorable results obtained in the study.

Parameters irradiance, wave length, and total dose of energy have not been established yet. For light laser sources, the used doses were 60-250 J/cm², whereas for broad spectrum light sources they were 3—540 J/cm². ⁷⁰

Therefore, topical PDT should be considered in the treatment of recalcitrating viral warts, especially when the site, size or number of lesions limits the use of conventional therapies. The advantages are: minimal systemic toxicity, non-invasive treatment, good cosmetic result. Limitations refer to high cost, time spent and pain management.

GENITAL WARTS

Most destructive therapeutic modalities of anogenital condyloma such as electrocauterization or laser CO² vaporization destroy only the visible part of the warts, whereas subclinical lesions persist and frequently cause the recurrence of the lesion. ALA-PDT presents an advantage in selective destruction of these subclinical lesions, supporting the reduction of the high recurrence rate.

Fehr et al. 65 studied fluorescence of PpIX after application of ALA in condyloma acuminatum of 22 patients. Three to six hours after, fluorescence was homogeneously distributed on the epidermis. In a study of a series of cases carried out by Stefanaki et al. 71 in 12 male patients with condyloma acumimatum treated with PDT (ALA 6-11 hours, 400-800 nm,70-100 J/cm², 70 mw cm^-2), 73% of the patients presented complete responses.

Wang et al. carried out an open study with 164 patients in which 95% of the lesions improved after one to four sessions of ALA-PDT (ALA 3 hours, 630 nm, 100 J/cm^-2, 100 mW cm^-2). ⁷² In the 6-24 month follow-up, only 5% of the lesions recurred.

Less favorable results with ALA-PDT (ALA 5 hours, 630 nm, 37 J/cm^-2, 68 mW cm^-2) were observed in 9 men with genital condyloma resistant to conventional therapies with improvement in only 3 patients after 4 sessions ⁷³.

Topical PDT may be considered as a therapeutic option for patients with genital warts. Maybe the combination with other conventional ablative treatments can contribute for the reduction of the recurrence of lesions because of selective destruction of subclinical lesions of PDT.

MORPHEA

Morphea consists in a condition of chronic inflammatory reaction of the skin in which after the inflammatory stage there is circumscribed sclerosis of the skin. Despite the favorable prognosis of most cases, disseminated lesions may lead to contractions of the joints and immobilization.

Karrer et al. carried out a clinical observational study with 10 patients that presented morphea lesions resistant to treatment with PUVA bath and local therapies ⁷⁴. They were submitted to an average of 26 ± 8 sessions of ALA-PDT (ALA gel 3% for 6 hours, broad spectrum light PDT 1200 L, 40 mW cm^-2, 10 J/cm^-2) in weekly or biweekly sessions. Assessment of the level of sclerosis was made using clinical score and a durometer. In all patients, there was significant improvement in the two parameters in the end of treatment. As an adverse event, they reported mild hyperpigmentation in the treated area. In the two-year follow-up, there was no recurrence or progression of the lesions, but some patients developed new lesions in areas not treated with PDT. The action mechanism that was proposed by the same group seemed to be related with the induction of matrix metalloproteinase (MMP-1 and MMP-3) by fibroblasts after PDT ⁷⁵. Moreover, release of IL-1 by keratinocytes after PDT induces through a paracrine action the production of metalloproteinase by dermal fibroblasts ⁷⁶.

More recently, some studies with the application of PDT have been carried out with other skin conditions, such as photoaging, fungoid mycosis, and Kaposi sarcoma.

PHOTOREJUVENATION

Owing to the increase in searching for less invasive but effective procedures for the process of rejuvenation, new non-ablative processes and techniques have been used. Many recent studies have shown improvement of photodamaged skin and neocollagenese with the use of vascular lasers, infrared, pulsed intense light, nonablative radiofrequency and fractioned resurfacing. One of the most recent methods introduced in the dermatologic practice is the process of photorejuvenation with photodynamic therapy. Many studies were carried out with the use of photosensitizing drugs and pulsed dye laser (PDL) ⁷⁷. To present, molecular mechanisms that explain rejuvenation with PDT are far from being recognized. The understanding of the mechanisms involved in PDT as well as the interactions between light - photosensitizing agent – tissue are absolutely necessary to improve the selection of patients as well as to indicate PDT as treatment against skin aging.

Based on the observation that PDT effects on the face showed satisfactory cosmetic outcomes, the technique is used to that end, and there is improvement of the skin texture and it is considered today a potential therapy for photorejuvenation. In this sense, some investigators started different therapeutic attempts to transform PDT-ALA into a more attractive technique to cosmetic applications. Touma et al. reduced the time of application of ALA to 1, 2 and 3 hours associated with the same protocol for lighting with blue light ⁷⁸. The authors observed that reduced time of incubation proved to be as effective as the original protocol of 14-18 hours. In 2002, Ruiz-Rodriguez et al introduced the term photodynamic photorejuvenation ⁷⁹. The authors assessed the combination of PDL associated with 5-ALA (20% cream formulation) to treat the face with AKs and signs of aging. After two sessions of treatment, with 30-day intervals, the authors observed 91% cure of AK and excellent cosmetic global effect on the face. Gold used the combination PDL and ALA in a short incubation period (between 30 and 60 minutes), 3 treatment sessions with monthly intervals and observed improvement of 90% of periocular wrinkles, 100% texture, 90% pigmentation, 70% telangiectasia, and 83% cure of AK ⁸⁰. Avram et al observed 68% cure of AKs, 55% improvement of facial telangiectasias, 48% of pigmentation and 25% of texture, after one single sessions of PDL and ALA incubated for 1 hour ⁸¹.

In 2005, Dover et al observed superior efficacy of PDL-ALA over isolated PDL in a prospective randomized study ⁸². The results showed improvement of global aging on the side treated with PDL-ALA in relation to the other treated side with isolated PDL. The authors also reported adverse events and tolerance to treatment similar in both sides. In another pilot study, Torezan et al. studied the effect of PDL associated with ALA incubated for 2 hours under occlusion through histopathology before and after one single treatment ⁸³. Patients were submitted to treatment with PDL (Photoderm ESC-Sharplan, USA) with cut-off filter 615 nm, flow of 40 J/cm², triple pulse 7 ms and interval between the pulses of 2 ms. The patients received one application all over the face and 2 applications on additional areas where AKs were evident. The recovery time was up to 30 days, and there was improvement of global aging of the face and clinical cure of 100% of AKs. The histopathological assessment showed reduction of atypia of keratinocytes, reorganization and synthesis of the collagen on the superficial dermis, but there was no effect observed in sun elastosis. It is interesting to note that many AKs of the study started to have recurrence right after the completion of treatment, which was of 6 months (interval between the biopsies).

Mamur et al, in 2005, studied that abnormalities of collagen with electron microscopy, in patients submitted to two treatments with ALA-PDL or isolated PDL ⁸⁴. In this study, the authors observed increase in collagen type I in both groups, but it was more marked in the group previously treated with ALA.

In 2007, Zane et al assessed the use of MAL and continuous red light (LED 635 nm) in the treatment of photodamaged skin ⁸⁵. After 2 sessions, there was cure of AKs in 89% and considerable reduction of level of photodamage in patients. The echographic assessment of the skin showed significant increase in dermis thickness. However, telangectasia, hyperpigmentation and deep wrinkles did not show significant response ⁸⁶.

To present, photorejuvenation using PDT should be considered as a off-label application, The effect of rejuvenation induced by PDT is secondary and should be used in patients with multiple AKs on the face (Figure 5). To produce a good response, we should expect a typical reaction of PDT, that is, erythema, edema and desquamation. After the success of initial treatment, other techniques may be combined such as fractioning and ablative resurfacing, chemical peelings and pulsed intense light.

FUNGOID MYCOSIS

The use of PDT in the treatment of initial lesions in plaques of fungoid mycosis (FM) seems to show good results with the use of systemic photosensitizing agents. HPD drug is capable of photosensitizing the lymphocytes of patients with FM and inhibit their proliferation, similarly to PUVA 16. The use of topical drugs such as ALA and MAL seem to show variable results after multiple sessions ⁸⁶. New studies are necessary to define the real participation of PDT in treating FM.

KAPOSI SARCOMA

The use of systemic PDT such as sodium porphymer showed efficacy in the treatment of superficial and nodular lesions of Kaposi sarcoma (KS) with few adverse effects and excellent final cosmetic results 87. The protocols, however, range and may induce to blisters, edema, scars, hyperpigmentation and systemic symptoms resulting from marked aggression of tumors. There is therapeutic potential because in general the responses are similar to that of other methods already used in KS ^88,89.

CLOSING REMARKS

Based on what was shown above, we have shared a general approach of PDT in dermatology, especially in cutaneous oncology. For the past 5 years, the method went from investigational to a reality in dermatological therapy.

To obtain the best results, it is necessary to correctly follow the steps in the application of the method. Thus, using protocols already published and herein presented, correct light sources and above all, the correct indication of PDT, we may reach very high cure rates and excellent cosmetic results, as shown in publications of PDT. Recently, PDT with MAL was used in patients with actinic cheilitis and they reached complete response in 47% and partial response in another 47% ⁹⁰.

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Publication Dates

• Publication in this collection
  07 Jan 2010
• Date of issue
  Oct 2009