**5. Clinical results**

The fundamental difference between ALA and its methyl ester (MAL) is the more hydrophobic character of the MAL. Thus, MAL can better penetrate through the cell membranes and more easily reaches the deepest epidermal layers. However, the biosynthesis of protoporphyrin IX production from MAL is slightly more time consuming because of the need of hydrolysis of

Chlorin is a photosensitizer indicated in the cases of PDT using *i.v.* medication. It is derived from natural or synthetic tetrapyrroles, and an important feature is their strong light absorption in the spectralregionusuallyabove660nm.AsignificantadvantageofPDTusingchorinsisthereduced

Recently, eight new chlorins with amphiphilic properties were synthesized from PpIX. Biological studies of some of these new chlorins indicate the great potential of these com‐

Distinct light sources can be used for PDT. For therapy, the tissue must be irradiated with light at appropriate wavelengths (within the absorption spectrum of porphyrins). The porphyrins exhibit a very typical absorption spectrum with the highest peak at approximately 405 nm, called the Soret-band. Other lower absorption peaks, the Q-bands, are centered at 510, 545, 580 and 630 nm. The absorption band at 630 nm is preferentially used for irradiation since light at the red spectrum results in a higher skin penetration. Lasers and incoherent light sources (lamps, light-emitting-diode – LED – lamps and, intense pulsed light – IPL) have been used. When endoscopic applications are necessary, the activating light has to be delivered through optical fibers, and laser systems are the best option for this purpose. For dermatological application, incoherent light sources are more attractive, due to the possibility of distinct

The therapeutic efficacy of PDT involves administration to the patient of a photosensitizer or a pro-drug, a waiting time to allow adequate concentration of the sensitizer molecules in the tumor, and irradiation of the target tissue with a proper wavelength to activate the photosen‐ sitizer generating cytotoxic products, mainly the singlet-oxygen. To trigger cell death, a minimum number of singlet-oxygen molecules have to be produced. The minimal energy dose required to achieve the irreversible tissue damage, resulting in tumor necrosis, is called the

delivered to the tissue per unit area. Light intensity is measured in Watts (W) and corresponds to the energy per unit of time. One W corresponds to 1 J per 1 second. Irradiance is measured

surface [19, 21-22]. A simple relationship between light dose (D), irradiance (I) and time (t) is:

), that is the amount of energy

), representing the light power delivered to the tissue

duration of cutaneous photosensitivity as compared with other photosensitizers [16].

this compound.

236 Highlights in Skin Cancer

**4. Dosimetry**

threshold dose.

pounds as photosensitizers in PDT [17].

emission geometries and comparable lower cost [18-20].

The energy dose is given in Joules per centimeter square (J/cm2

in Watts per centimeter square (W/cm2

Nonmelanoma skin cancer is the most frequent one in the world population. Currently, therapeutic options are surgical ressection, electrocoagulation, curettage, cryotherapy, immunomodulating agents, cytotoxic agents, chemotherapy, PDT, among others. PDT is a noninvasive technique with excellent cosmetic outcome, well tolerated by patients and with good healing results, when used for the initial stages of cancer lesions. Different studies show the technique effectiveness for BCC (Figure 3 and 4), presenting curative rates ranging from 52.2% to 100% [7, 23-28].

**Figure 3.** Nodular BCC before (A) and 30 days after (B) PDT, treated with MAL 20% in 2 sessions and dose of 100J/cm2

**Figure 4.** Superficial BCC before (A) and 30 days after (B) PDT, treated with MAL 20% in 2 sessions and dose of 100J/cm2

Wolf et al., (1993), in their study treated 70 different lesions – superficial BCC, actinic keratosis (AK), nodular-ulcerative BCC, squamous cell carcinoma (SCC) and melanoma – using ALA cream, with dose of 30J/cm² for superficial BCC and AK and 100 J/cm²-300 J/cm² for other lesions. Results at 12 months showed complete response for AK, 36 of 37 superficial BCC lesions showed good responses, 5 of 6 SCC, 8 cutaneous metastases of malignant melanoma were therapeutic failures and other lesions showed a partial response after treatment [23]. In the study by Calzavara (1994), which also included several lesions (AK, BCC, nodular BCC, pigmented BCC and SCC), all treated with ALA 20%, there were complete response in 100% for BCC and AK cases, decreasing to 80% in nodular lesions. Other treated lesions exhibited low curative rate when evaluated 30 days after treatment. These curative rates decreased to 86.9% in BCC and 50% in nodular BCC in the clinical follow-up done for 29 months [27]. According to the study of Souza et al., (2009), after evaluating 20 patients (showing difficulties, impediment high risk or rejection of surgical procedure) with BCC and Bowen's disease (BD) treated with ALA 20%, irradiated at wavelength of 630 nm and doses of 100 to 300 J\cm², showed that, after 1 session, presented curative rates of 91.2% at three months and 57.7% at sixty months [7].

Caekelberg et al., (2009), observed the PDT result after 6 months in 90 patients with superficial BCC of approximately diameter 10 mm. The complete response rate was of 88.1% with cosmetic

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239

Interesting results were achieved in the study of Surrenti et al., (2008), where they evaluated the PDT response in nodular and superficial BCC. In this study, 118 lesions were treated in 69 patients, located at the chest, face, head, neck and limbs. Superficial BCC were diagnosed in 94 lesions and 24 showed nodular BCC lesions, confirmed by histology. Complete response was obtained in 84/94 (89.4%) at superficial BCC, and in 12/23 (52.2%) at nodular BCC, when evaluated at 30 days after the second session. The cosmetic outcome was evaluated as excellent

Szeimies et al., (2008), compared PDT with surgery to treat superficial BCC between 8-20 mm size, in 196 patients with 234 lesions. The lesions treated with MAL 160 mg/g, in two sessions, showed a curative rate of 92.2% compared to 99.2% of the lesions treated with surgery, when assessed after 3 months of treatment. After 12 months, the cosmetic outcome was considered by the investigator as good or excellent in 92.8% of patients treated with PDT versus 51.2% of patients treated with surgery. The recurrence was 9.3% in comparison with 0% for lesions treated with PDT and surgery, respectively [26]. In nodular BCC treatment curative rates, after three months, of 91% with PDT versus 98% with surgery were obtained. After 12 months, 96% of lesions treated with surgery showed complete response compared to the 83% of the lesions treated with PDT. This study was performed on 97 patients with 105 lesions, all confirmed by

In a recent study, (2012), was compared PDT with surgery, in 72 patients with 94 lesions superficial and nodular BCC with a maximum 3 mm thick. The patients were separated into two groups according to their choice of treatment, being 48 lesions treated with PDT and 46 with surgery. After 3 months, the curative rate was 95.83 % with PDT versus 95.65% with surgery. The recurrence rate was, after 12 months, 4.16% for PDT compared to 4.34% for

Basset-Seguin et al., (2008) presented results comparing PDT with cryotherapy in 118 patients. The authors used PDT protocol with MAL and two sessions separated by 7 days. The complete clinical response, after 3 months of treatment, was of 97% with cryotherapy versus 95% with PDT. Comparing the cosmetic outcome, they obtained excellent and good response in 54%

Another multicenter study made by Aguilar et al., (2010), compared imiquimod and PDT with surgeryinthetreatmentof54Bowen'sdiseaselesions(63%)and32superficialBCClesions(37%). After 24 months, the curative rate was of 97.5% for surgery, 89.5% for PDT, and 87.5% for imiquimod. The surgery cost was approximately twice the value when compared to PDT [34].

The differences between the curative results obtained in the different studies is mainly due to the distinct treament protocols: a) different lesion selection criteria (diameter, length, thickness, site, previous treatment); b) no standardization of the pre-PDT procedures (shaving, curettage, scarification); c) distinct drugs (ALA, MAL); d) different cream incubation times (2, 3 and 4

outcome qualified as excellent in 96.25% of patients [25].

in 83% of cases and good in the remaining 17% of the cases [28].

versus 93% with cryotherapy and PDT, respectively [33].

histopathology [31].

surgery [32].

Horn et al., (2003), treated 94 patients with 108 superficial, nodular and mixed BCC lesion with difficult to treatment (resulting scars from reconstructive surgery extensive, interfering with normal function of eyelids or lips, or postoperative infections), finding complete response after 3 months in 92% of superficial BCC and 87% of nodular BCC. The cosmetic outcome was evaluated as excellent or good by investigators in 76% of the lesion after 3 months follow-up, increasing to 85% at 12 months and 94% at 24 months follow-up [29].

A recent study comparing CO2 laser ablation *versus* PDT in immunocompetent patients with multiple AK concluded that both treatments were effective in reduction of AK, but PDT seems to be superior in terms of reduction of the affected area and overall satisfaction by patients and clinicians [30].

Foley et al., (2009), conducted a double-blind and placebo-controlled study in primary lesion of nodular BCC (up to 5 mm in depth) in two medical centers. MAL was used at concentration of 160 mg/g cream or placebo cream, with three hours of occlusion. The light source applied was in the range of 570-670 nm, with an irradiance of 50-200 mW/cm² and dose of 75 J/cm². In total, 131 patients with 150 lesions were included in the study, 66 patients with 75 lesions were treated with MAL cream and 65 patients with 75 lesions with placebo cream. The treatment was developed in cycles. The first cycle was conducted in two sessions, with one week interval between sessions. If the response was partial (≤50% reduction in greatest diameter) after 3 months follow-up, the second cycle was initiated with two more sessions with one week interval, and monitoring the patient for six months. If the answer was not complete, the responsible medical team indicated the patient for surgical procedure. The complete response after 6 months follow-up, with MAL was of 73% (55/75 lesions) versus 27% (20/75 lesions) with placebo. The response decreases in larger lesion (≥ 10mm in diameter and ≥ 1mm of baseline depth). The cosmetic outcome of the lesions treated with MAL-PDT was good or excellent in 98% of the cases [24].

Caekelberg et al., (2009), observed the PDT result after 6 months in 90 patients with superficial BCC of approximately diameter 10 mm. The complete response rate was of 88.1% with cosmetic outcome qualified as excellent in 96.25% of patients [25].

Wolf et al., (1993), in their study treated 70 different lesions – superficial BCC, actinic keratosis (AK), nodular-ulcerative BCC, squamous cell carcinoma (SCC) and melanoma – using ALA cream, with dose of 30J/cm² for superficial BCC and AK and 100 J/cm²-300 J/cm² for other lesions. Results at 12 months showed complete response for AK, 36 of 37 superficial BCC lesions showed good responses, 5 of 6 SCC, 8 cutaneous metastases of malignant melanoma were therapeutic failures and other lesions showed a partial response after treatment [23]. In the study by Calzavara (1994), which also included several lesions (AK, BCC, nodular BCC, pigmented BCC and SCC), all treated with ALA 20%, there were complete response in 100% for BCC and AK cases, decreasing to 80% in nodular lesions. Other treated lesions exhibited low curative rate when evaluated 30 days after treatment. These curative rates decreased to 86.9% in BCC and 50% in nodular BCC in the clinical follow-up done for 29 months [27]. According to the study of Souza et al., (2009), after evaluating 20 patients (showing difficulties, impediment high risk or rejection of surgical procedure) with BCC and Bowen's disease (BD) treated with ALA 20%, irradiated at wavelength of 630 nm and doses of 100 to 300 J\cm², showed that, after 1 session, presented curative rates of 91.2% at three months and 57.7% at

Horn et al., (2003), treated 94 patients with 108 superficial, nodular and mixed BCC lesion with difficult to treatment (resulting scars from reconstructive surgery extensive, interfering with normal function of eyelids or lips, or postoperative infections), finding complete response after 3 months in 92% of superficial BCC and 87% of nodular BCC. The cosmetic outcome was evaluated as excellent or good by investigators in 76% of the lesion after 3 months follow-up,

A recent study comparing CO2 laser ablation *versus* PDT in immunocompetent patients with multiple AK concluded that both treatments were effective in reduction of AK, but PDT seems to be superior in terms of reduction of the affected area and overall satisfaction by patients and

Foley et al., (2009), conducted a double-blind and placebo-controlled study in primary lesion of nodular BCC (up to 5 mm in depth) in two medical centers. MAL was used at concentration of 160 mg/g cream or placebo cream, with three hours of occlusion. The light source applied was in the range of 570-670 nm, with an irradiance of 50-200 mW/cm² and dose of 75 J/cm². In total, 131 patients with 150 lesions were included in the study, 66 patients with 75 lesions were treated with MAL cream and 65 patients with 75 lesions with placebo cream. The treatment was developed in cycles. The first cycle was conducted in two sessions, with one week interval between sessions. If the response was partial (≤50% reduction in greatest diameter) after 3 months follow-up, the second cycle was initiated with two more sessions with one week interval, and monitoring the patient for six months. If the answer was not complete, the responsible medical team indicated the patient for surgical procedure. The complete response after 6 months follow-up, with MAL was of 73% (55/75 lesions) versus 27% (20/75 lesions) with placebo. The response decreases in larger lesion (≥ 10mm in diameter and ≥ 1mm of baseline depth). The cosmetic outcome of the lesions treated with MAL-PDT was good or excellent in

increasing to 85% at 12 months and 94% at 24 months follow-up [29].

sixty months [7].

238 Highlights in Skin Cancer

clinicians [30].

98% of the cases [24].

Interesting results were achieved in the study of Surrenti et al., (2008), where they evaluated the PDT response in nodular and superficial BCC. In this study, 118 lesions were treated in 69 patients, located at the chest, face, head, neck and limbs. Superficial BCC were diagnosed in 94 lesions and 24 showed nodular BCC lesions, confirmed by histology. Complete response was obtained in 84/94 (89.4%) at superficial BCC, and in 12/23 (52.2%) at nodular BCC, when evaluated at 30 days after the second session. The cosmetic outcome was evaluated as excellent in 83% of cases and good in the remaining 17% of the cases [28].

Szeimies et al., (2008), compared PDT with surgery to treat superficial BCC between 8-20 mm size, in 196 patients with 234 lesions. The lesions treated with MAL 160 mg/g, in two sessions, showed a curative rate of 92.2% compared to 99.2% of the lesions treated with surgery, when assessed after 3 months of treatment. After 12 months, the cosmetic outcome was considered by the investigator as good or excellent in 92.8% of patients treated with PDT versus 51.2% of patients treated with surgery. The recurrence was 9.3% in comparison with 0% for lesions treated with PDT and surgery, respectively [26]. In nodular BCC treatment curative rates, after three months, of 91% with PDT versus 98% with surgery were obtained. After 12 months, 96% of lesions treated with surgery showed complete response compared to the 83% of the lesions treated with PDT. This study was performed on 97 patients with 105 lesions, all confirmed by histopathology [31].

In a recent study, (2012), was compared PDT with surgery, in 72 patients with 94 lesions superficial and nodular BCC with a maximum 3 mm thick. The patients were separated into two groups according to their choice of treatment, being 48 lesions treated with PDT and 46 with surgery. After 3 months, the curative rate was 95.83 % with PDT versus 95.65% with surgery. The recurrence rate was, after 12 months, 4.16% for PDT compared to 4.34% for surgery [32].

Basset-Seguin et al., (2008) presented results comparing PDT with cryotherapy in 118 patients. The authors used PDT protocol with MAL and two sessions separated by 7 days. The complete clinical response, after 3 months of treatment, was of 97% with cryotherapy versus 95% with PDT. Comparing the cosmetic outcome, they obtained excellent and good response in 54% versus 93% with cryotherapy and PDT, respectively [33].

Another multicenter study made by Aguilar et al., (2010), compared imiquimod and PDT with surgeryinthetreatmentof54Bowen'sdiseaselesions(63%)and32superficialBCClesions(37%). After 24 months, the curative rate was of 97.5% for surgery, 89.5% for PDT, and 87.5% for imiquimod. The surgery cost was approximately twice the value when compared to PDT [34].

The differences between the curative results obtained in the different studies is mainly due to the distinct treament protocols: a) different lesion selection criteria (diameter, length, thickness, site, previous treatment); b) no standardization of the pre-PDT procedures (shaving, curettage, scarification); c) distinct drugs (ALA, MAL); d) different cream incubation times (2, 3 and 4 hours); e) distinct irradiation parameters; f) number of sessions; g) different treatment evaluation times (1, 3 or 6 months) and time to evaluate recurrence (6 months, 1, 3, 5 or 10 years) [35]. However, thicker lesions and nodular BCC present lower curative rates when compared to superficial BCC [26, 28, 33, 35]. Furthermore, pretreatment procedures as shaving or curettage [29], and multiple sessions [15, 36] can increase positive response to PDT [35].

According to Basset-Seguin et al., (2008), recurrence after 5 years of PDT in 103 superficial BCC, using MAL, was of 22%, all present in the first three years after treatment. This rate is compa‐ rable with the one obtained in patients treated with cryotherapy [33]. In the study by Mosterd et al., (2008), 83 nodular BCC were treated with 20% ALA-PDT and fractionated irradiation with a total dose of 150J/cm². A recurrence rate of 30.3% were obatined after 3 years. In this study, the thicknesses of 78 lesions were measured and an increased failure risk was present in thicker lesions, over 1.3 mm (42.2%), when compared to the thinner ones (15,5%) [42]. In a study by Rhodes et al., (2004), 53 nodular BCC, treated with MAL-PDT, a recurrence rate of 14% was observed after 5 years of treatment. A recurrence in 5/40 lesions treated with one PDT session and 2/9 treated with two PDT sessions, occuring especially in the first two years of treatment. When compared with surgery, the recurrence rate decreases to 4% [31]. Similar results were reported in a study of Szeimies et al., (2008), with recurrence rates for PDT of 9.3%

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Another study evaluating 157 BCC lesions (111 superficial BCC, 40 nodular BCC and 6 histology missing) in 90 patients treated with two sessions of MAL-PDT, recurrence rates estimated of 7% in the first 3 months, 19% in 6 months, 27% in 12 months and 31% in 24 months after treatment were obtained. When comparing recurrence rates at 12 months of nodular and

Christensen et al, (2009), classified 60 BCC (24 nodular BCC e 36 superficial BCC), according to size, as smaller than 1 cm, between 1-2 cm and larger than 2 cm. All lesions were curetted and DMSO was applied at the site for 5 min, then 20% ALA cream was applied and kept in position for 3 hours. PDT procedure was performed in one or two sessions. After 6 years follow up, 43/53 (81%)oflesionsstillshowedcompleteresponse.Fivepatientswereexcludedforpresentingpartial response to treatment in the first three months and two patients died at the onset of follow-up periodfromcausesunrelatedtostudy.Therecurrenceswerepresentbeforethreeyears,withtwo thirds of these presented in the first 12 months. The average age of the patients with recurrence was of 76 y.o. for men and 77 for women. Considering lesion size, no statistical difference was observedbecauseonlyonelesionmeasuredmorethan2cm[45].Thefollowupof10years,showed an overall curative rate of 75%, 60% for lesions treated with one session and 81% for two ses‐

Multiple factors have been associated with recurrence in the different studies. Few sessions are associated with high recurrence rates. One PDT session is the major factor for treatment failure [33, 44, 46]. In the study by Soler et al., (2001), 33 lesions presented recurrence, 29 of them treated with a single session and four treated with two sessions [46]. Similar data were found by Christensen et.al., (2009), where 43/53 lesions remained disease-free; 68% after one

Size and thickness are factors that also affect lesion recurrence. The study by Mosterd et al., (2008), presented recurrence rates of 42% in the lesions with ≥ 1,3 mm thickness, and of 15.5% for lesions ≤ 1,3 mm. Horn et al., (2003), showed an increased recurrence associated with lesion size when evaluated 24 months after treatment. Lesions of 0-15 mm presented 4% recurrence,

and 0% for surgery, in a follow-up of 12 months [24].

superficial BCC the rates were of 28% versus 13%, respectively [43].

sions, all recurrence cases were presented in the first three years [44].

treatment session and 91% after two treatment session [45].

increasing to 16% in lesions of 16-30mm and greater than 30mm, 33% [29].

PDT may present some adverse reactions such as photosensitivity, infection, erythema, edema, pain, among others [24, 37]. In topical PDT, the photosensitive drug is localized in lesion and consumed after irradiation. Reports of local photosensitivity after treatment are scarce, and when present, are present in the following 24 hours after irradiation. The systemic PDT, on the other hand, has a longer photosensitivity time [23]. Infection is a complication that almost does not occur due to the proven action of PDT for microbiological control [37]. However, some factors may predispose to this occurrence, such as, diabetes, peripheral vascular disease, and others. In a study by Wolfe et al., (2007), 700 AK lesions were treated with PDT and only 4 cases of cellulitis were reported, but easily controled by antibiotic therapy [38]. Changes in pigmentation, hyper and hypopigmentations, are reported in literature as approximately 1% of all adverse reactions [37]. The pain may be present during irradiation or within 7 days after treatment. In the study by Morton et al., (2001), only one third of patients treated had pain qualified between moderate and severe [39]. In the experiment by Ibbotson et al., (2011), during 9 years, different lesions were trated with topical PDT, 16% of patients showed severe pain and 50% moderate pain [37]. In a multicenter, randomized, controlled and open study, comparing PDT with surgery it was found that for PDT, 37/100 (37%) of patients had an adverse reaction versus 14/96 (14,6%) of patients treated with surgery. For PDT, photosensitivity reaction, which includes sensations of discomfort, burning and erythema was the most frequent, these reactions were of mild to moderate intensity and easily treated. For surgery, the more expected reaction was infection, that occured in 5 of the 14 patients and requiring the use of systemic antibiotics for two weeks [26].

PDT can be associated with other treatment techniques, such as surgery, as described by Willey et al., (2009). In this study, surgical ressection was associated with PDT with 20% ALA for recurrence prevention. The PDT protocol consisted of an hour of inoculation and illumination with a light source with wavelength at 417 nm during 1000 seconds (irradiance of 10 mW/cm²). The PDT cycles were repeated every 1-2 months for two years. In the first year after first PDT session, average reduction of lesions appearance was around 80%, reaching values of 95% reduction by the end of the second year [40].

The recurrence of BCC lesions when treated with traditional techniques has been estimated of 36% after one year of treatment, 61% after two years and 18% after 6 to 10 years of treatment [41]. For PDT, several studies have been published assessing the lesion recurrence after 1 to 5 [7, 15, 33, 42-43], 6 and 10 years of treatment [44].

In the clinical study done by Souza et al., (2009), the treated patients were monitored (or followed) for 60 months. The lesion recurrence was presented in 11/26 lesions (42.3%), the recurrence depending on the lesion types were of 2/5 for nodular BCC, 2/6 for superficial BCC and 7/15 to Bowen's disease [7].

According to Basset-Seguin et al., (2008), recurrence after 5 years of PDT in 103 superficial BCC, using MAL, was of 22%, all present in the first three years after treatment. This rate is compa‐ rable with the one obtained in patients treated with cryotherapy [33]. In the study by Mosterd et al., (2008), 83 nodular BCC were treated with 20% ALA-PDT and fractionated irradiation with a total dose of 150J/cm². A recurrence rate of 30.3% were obatined after 3 years. In this study, the thicknesses of 78 lesions were measured and an increased failure risk was present in thicker lesions, over 1.3 mm (42.2%), when compared to the thinner ones (15,5%) [42]. In a study by Rhodes et al., (2004), 53 nodular BCC, treated with MAL-PDT, a recurrence rate of 14% was observed after 5 years of treatment. A recurrence in 5/40 lesions treated with one PDT session and 2/9 treated with two PDT sessions, occuring especially in the first two years of treatment. When compared with surgery, the recurrence rate decreases to 4% [31]. Similar results were reported in a study of Szeimies et al., (2008), with recurrence rates for PDT of 9.3% and 0% for surgery, in a follow-up of 12 months [24].

hours); e) distinct irradiation parameters; f) number of sessions; g) different treatment evaluation times (1, 3 or 6 months) and time to evaluate recurrence (6 months, 1, 3, 5 or 10 years) [35]. However, thicker lesions and nodular BCC present lower curative rates when compared to superficial BCC [26, 28, 33, 35]. Furthermore, pretreatment procedures as shaving or curettage [29], and multiple sessions [15, 36] can increase positive response to PDT [35].

PDT may present some adverse reactions such as photosensitivity, infection, erythema, edema, pain, among others [24, 37]. In topical PDT, the photosensitive drug is localized in lesion and consumed after irradiation. Reports of local photosensitivity after treatment are scarce, and when present, are present in the following 24 hours after irradiation. The systemic PDT, on the other hand, has a longer photosensitivity time [23]. Infection is a complication that almost does not occur due to the proven action of PDT for microbiological control [37]. However, some factors may predispose to this occurrence, such as, diabetes, peripheral vascular disease, and others. In a study by Wolfe et al., (2007), 700 AK lesions were treated with PDT and only 4 cases of cellulitis were reported, but easily controled by antibiotic therapy [38]. Changes in pigmentation, hyper and hypopigmentations, are reported in literature as approximately 1% of all adverse reactions [37]. The pain may be present during irradiation or within 7 days after treatment. In the study by Morton et al., (2001), only one third of patients treated had pain qualified between moderate and severe [39]. In the experiment by Ibbotson et al., (2011), during 9 years, different lesions were trated with topical PDT, 16% of patients showed severe pain and 50% moderate pain [37]. In a multicenter, randomized, controlled and open study, comparing PDT with surgery it was found that for PDT, 37/100 (37%) of patients had an adverse reaction versus 14/96 (14,6%) of patients treated with surgery. For PDT, photosensitivity reaction, which includes sensations of discomfort, burning and erythema was the most frequent, these reactions were of mild to moderate intensity and easily treated. For surgery, the more expected reaction was infection, that occured in 5 of the 14 patients and requiring the

PDT can be associated with other treatment techniques, such as surgery, as described by Willey et al., (2009). In this study, surgical ressection was associated with PDT with 20% ALA for recurrence prevention. The PDT protocol consisted of an hour of inoculation and illumination with a light source with wavelength at 417 nm during 1000 seconds (irradiance of 10 mW/cm²). The PDT cycles were repeated every 1-2 months for two years. In the first year after first PDT session, average reduction of lesions appearance was around 80%, reaching values of 95%

The recurrence of BCC lesions when treated with traditional techniques has been estimated of 36% after one year of treatment, 61% after two years and 18% after 6 to 10 years of treatment [41]. For PDT, several studies have been published assessing the lesion recurrence after 1 to 5

In the clinical study done by Souza et al., (2009), the treated patients were monitored (or followed) for 60 months. The lesion recurrence was presented in 11/26 lesions (42.3%), the recurrence depending on the lesion types were of 2/5 for nodular BCC, 2/6 for superficial BCC

use of systemic antibiotics for two weeks [26].

240 Highlights in Skin Cancer

reduction by the end of the second year [40].

[7, 15, 33, 42-43], 6 and 10 years of treatment [44].

and 7/15 to Bowen's disease [7].

Another study evaluating 157 BCC lesions (111 superficial BCC, 40 nodular BCC and 6 histology missing) in 90 patients treated with two sessions of MAL-PDT, recurrence rates estimated of 7% in the first 3 months, 19% in 6 months, 27% in 12 months and 31% in 24 months after treatment were obtained. When comparing recurrence rates at 12 months of nodular and superficial BCC the rates were of 28% versus 13%, respectively [43].

Christensen et al, (2009), classified 60 BCC (24 nodular BCC e 36 superficial BCC), according to size, as smaller than 1 cm, between 1-2 cm and larger than 2 cm. All lesions were curetted and DMSO was applied at the site for 5 min, then 20% ALA cream was applied and kept in position for 3 hours. PDT procedure was performed in one or two sessions. After 6 years follow up, 43/53 (81%)oflesionsstillshowedcompleteresponse.Fivepatientswereexcludedforpresentingpartial response to treatment in the first three months and two patients died at the onset of follow-up periodfromcausesunrelatedtostudy.Therecurrenceswerepresentbeforethreeyears,withtwo thirds of these presented in the first 12 months. The average age of the patients with recurrence was of 76 y.o. for men and 77 for women. Considering lesion size, no statistical difference was observedbecauseonlyonelesionmeasuredmorethan2cm[45].Thefollowupof10years,showed an overall curative rate of 75%, 60% for lesions treated with one session and 81% for two ses‐ sions, all recurrence cases were presented in the first three years [44].

Multiple factors have been associated with recurrence in the different studies. Few sessions are associated with high recurrence rates. One PDT session is the major factor for treatment failure [33, 44, 46]. In the study by Soler et al., (2001), 33 lesions presented recurrence, 29 of them treated with a single session and four treated with two sessions [46]. Similar data were found by Christensen et.al., (2009), where 43/53 lesions remained disease-free; 68% after one treatment session and 91% after two treatment session [45].

Size and thickness are factors that also affect lesion recurrence. The study by Mosterd et al., (2008), presented recurrence rates of 42% in the lesions with ≥ 1,3 mm thickness, and of 15.5% for lesions ≤ 1,3 mm. Horn et al., (2003), showed an increased recurrence associated with lesion size when evaluated 24 months after treatment. Lesions of 0-15 mm presented 4% recurrence, increasing to 16% in lesions of 16-30mm and greater than 30mm, 33% [29].


**Author and type of study**

**Table 1.** Study results of topical PDT for non melanoma skin cancer

potential factors are gender and lesion site [43].

**7. Final considerations**

ressection or in high risk patients.

performance in cancer treatment.

**Treatment Procedure Study size Result**

A higher recurrence rate is also present at nodular BCC, when compared to the superficial BCC [43, 46]. Age can be a factor that increases the lesion recurrence treated with PDT, other

PDT is already approved for the treatment of actinic keratosis and basal cell carcinoma. Offlabel uses for PDT have been indicated for several dermatological conditions such as photodamaged skin, scleroderma, warts, cutaneous leishmaniosis, psoriasis, cutaneous T-cell lymphoma and acne [20, 47]. Infectious disease has the potential to become one of the main indications of PDT in Dermatology. The microbiological control of bacteria, fungi and protozoa ininfectedlesionshasbeenpresented[48-51].Onychomicosisisoneofthenewindications,where PDT presents good results even in cases where the antifungal systemic therapy failured (Paulada-Silva, A. et al., Fast elimination of onychomycosis by hematoporphyrin derivative-photody‐ namic therapy. Accepted by Photodiagnosis and Photodynamic Therapy on December2012).

PDT is a noninvasive technique, with few potential adverse reactions, that presents good curative rates and excellent cosmetic outcome. It may be chosen as a first option for patients with small lesions of nonmelanoma skin cancer, especially the ones in complex sites for surgical

PDT protocols and customized dosimetry for each target skin lesion still need to be defined. The development of new PDT drugs and delivery systems has the potential of increasing the curative rates of the present protocols. Instrumentation of light sources designed to adapt the emission geometry to the anatomical site characteristics is also important to improve PDT

The local treatment of infected lesions and cosmetics are PDT indications that have been fastly increasing. New protocols and drugs have been investigated, as well as new light devices

developed, making PDT in Dermatology an exciting and growing field.

**6. Non-oncological and off-label pdt applications in dermatology**

Recurrence at 12 mo 4.16% PDT 4.34% Surgery

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Photodynamic Therapy for Non-Melanoma Skin Cancer


**Table 1.** Study results of topical PDT for non melanoma skin cancer

**Author and type of study**

> MAL 160 mg/g Preparation prior PDT:

on all nodular.

Shaving.

MAL cream Preparation pre-PDT: Surface debridement

MAL 160 mg/g cream Preparation pre-PDT:

surface

ALA 20% DMSO 99%

MAL 160 mg/g Preparation pre-PDT:

ALA 20% cream

remove scales and crust of lesion

Preparation pre-PDT: curettage

Superficial lesions were debrided. Nodular lesions were curetted

Preparation pre-PDT: remove scales and crusts of lesion surface

MAL 160 mg/g cream

Debulking procedure was performed

Pre-PDT procedure in nodular lesions:

Soler et al., (2001) Retrospective study [46]

242 Highlights in Skin Cancer

Horn et al., (2003) Open-label study [29]

Basset –Seguin et al., (2008) Randomized, comparative, multicenter study [33]

Szeimies et al., (2008) multicentre, randomised, controlled, open study [26]

Christensen et al., (2009) and

Lindberg-Larsen et al., (2012) Retrospective study [43]

Cosgarea et al., (2012) prospective, comparative, controlled, clinical study [32]

Prospective study study

(2012)

[44-45]

**Treatment Procedure Study size Result**

Total: 310 lesion 131 sBCC

Total:108 lesions 49 sBCC 52 nBCC 7 mixed BCC

Total 201 lesions 103 sBCC with PDT 98 sBCC with cryotherapy

Total 196 lesions 100 sBCC with PDT 96 sBCC with surgery.

Total:60 lesion 24 sBCC 36 nBCC

Total: 157 lesion 111 sBCC 40 nBCC 6 unknown

Total 94 sBCC 48 lesions with PDT 46 lesions with Surgery

82 nBCC ≤ 2mm thickness 86 nBCC ≥2mm thickness

3 mo, Complete Response

3 mo, Complete Response

3 mo, Complete response

3 mo Complete response

3 mo, Complete response 92% total lesion 72 mo, Complete response 81% total lesion

120mo, Complete response

3 mo Complete response

3 mo Complete response

75% total lesion

93% lesion Recurrence at 12 mo: nBCC 28% sBCC 13%

95.83% PDT 95.65% Surgery

91% sBCC 93% nBCC thin 86% nBCC thick 11% Recurrence at 35 mo

92% sBCC 87% nBCC 57% mixed BCC 9% Recurrence at 12 mo 18% Recurrence at 24 mo

97% PDT 95% Cryotherapy Recurrence at 5 years

22% PDT 20% Cryotherapy

92.2% PDT 99.2% Surgery Recurrence at 12 mo

9.3% PDT 0% Surgery A higher recurrence rate is also present at nodular BCC, when compared to the superficial BCC [43, 46]. Age can be a factor that increases the lesion recurrence treated with PDT, other potential factors are gender and lesion site [43].
