Luiz Eduardo Garcia Galvão1, Heitor de Sá Gonçalves1, Antônio Renê Diógenes de Sousa1, Leonardo Augusto Coelho Torres da Silva1, Iana de Almeida Siqueira1
Actinic keratosis (AK) and non-melanoma skin cancer lesions, such as Bowen’s disease (BD) and superficial and nodular basal cellular carcinomas (BCC), are the most common malignant neoplasias in the world, particularly in the Caucasian population.These types of lesions account for more than 1/3 of all cancers in the United States, with approximately 900,000 to 1.2 million new cases per year.1 Such lesions present a good prognosis when treated early, since BCC – the most common non-melanocytic cutaneous neoplasia (NMCN) – rarely metastasizes, although it can be locally invasive if it is not treated. On the other hand, since squamous cell carcinoma (SCC) – which can develop from AK or BD lesions (in situ SCC) – can metastasize, all cases of AK and BD must be treated.2
Photodynamic therapy (PDT) uses a light source to activate a topical photosensitizer that has a high selectivity for the affected tissue (NCNM in this case). A 20% 5-aminolevulinic acid solution (5-ALA) was the first broadly used product to treat AK (initially in the United States) from the 1990s. It was used on the skin, with 14-hour incubation periods (later reduced to 1 hour) with sources of blue light (415 nm).3 European research also focused on the treatment of BCCs, with the development of methyl aminolevulinate hydrochloride (MAL) in cream, to be exposed to the skin for 3 hours, using a 632 nm red light.4 Both 5-ALA and MAL produce photoactive porphyrins with selectivity to the neoplasic tissue, causing necrosis and apoptosis following illumination.5-8
There are few studies in the literature comparing 5-ALA and MAL. MAL, however, is more lipophilic, and thus has greater penetration and could also be used in NCNM. Additionally, the treatment protocol for MAL is more standardized than that of 5-ALA, which uses several sources of light or adjuvant treatments (5-fluorouracil and dermabrasion before the sessions, for instance).Moreover, MAL uses red light with longer wavelengths, allowing a more effective penetration of the photosensitizer.
This study’s objective was to evaluate clinical and aesthetic responses and the more common side effects in patients who were treated with PDT-MAL sessions for facial AKs, superficial and nodular BCCs (less than 2 mm deep in the histological analysis and BD.
A prospective observational study was developed, following the ethical recommendations of the Declaration of Helsinki (2000), to include consecutive patients who sought care spontaneously at the Centro de Referência em Dermatologia Sanitária Dona Libânia in Fortaleza, Brazil. Patients had AK facial lesions, superficial or nodular BCCs less than 2mm deep, and BD (Graph 1). The selection criteria included the regular use of wide spectrum anti-UVA/UVB sunscreen and unsuccessful previous cryotherapy or 5-fluorouracil treatments for AK patients.
Skin scales were removed prior to the treatment by curettage or gauze soaked in 0.9% saline solution, without anesthesia. Hemostasis was carried out using compression only; the use of aluminium chloride solution or electrocoagulation was avoided, in order to prevent interference in the penetration of the MAL.A thick layer of MAL (Metvix®Galderma, Br was then applied on the lesion or area to be treated, and was covered by transparent PVC plastic film (Figure 1); aluminium foils resembling curative masks were affixed with adhesive micropored plaster (Figure 2).
After 2.5 to 3 hours, the curative mask was taken off and the MAL was removed with 0.9% saline solution. The treated area was immediately subjected to illumination with a 632 nm and 37 j/cm2 source of red light (Aktilite® CL128 Galderma, Br), positioned 5 to 8 cm from the treated area, for 8 minutes.
Patients (n = 102) included 59 with AK (58%), 32 with BCC (31%), and 11 with BD (11%).The 59 patients with facial AKs had one PDT-MAL session and were evaluated for clinical and aesthetic results after 12 weeks.The aesthetic result was considered satisfactory when the patient presented photorejuvenation with improvement of solar melanoses, telangiectasias and thin wrinkles. All patients presented satisfactory aesthetic results and a decrease in the number of AKs. Six patients needed one additional session after 12 weeks, due to an incomplete result (Graph 2 / Figures 3 and 4).
Of the 32 BCC patients who were treated with PDTMAL, all except 6 presented a histological cure and excellent aesthetic results after the treatment (Graph 3 / Figures 5 and 6). Of the remaining, 6 1 had superficial extensive facial BCC, 2 had Gorlin syndrome, and 3 had BCC lesions in the "H" area of the face (perioral, perinasal and periorbital areas). The 11 BD patients had 13 lesions treated with 2 PDT-MAL sessions with a 7-day interval. The lesions persisted in two patients after 12 weeks.The remaining patients presented a clinical and histological cure with excellent aesthetic results (Graph 4 / Figure 7).
All patients reported sensibility to pain during the procedure; the interruption of the illumination was necessary in only 2 cases. Several strategies were employed to minimize pain during the sessions: oral analgesic 1 hour before the use of the red light, cooling spray, thermal water, cooled saline solution compresses applied directly on the treated area during the entire period of illumination, and increasing the distance from the light bulb to the skin to 8 cm.9 A higher correlation of pain sensibility – which was directly proportional to the extent of the treated area (and, in the case of AKs, to the number of lesions) – was observed in male patients.The area most sensitive to the treatment was the scalp in bald men, followed by the frontal region in both genders.
An additional side effect observed was erythema, light or moderate in most cases, which was treated with emollients. It was severe in only one case, and required the use of a topical corticosteroid. Crusts and desquamation were commonly observed, while pustules and significant edema were observed in one female patient (Figure 8).
AKs are the most common premalignant cutaneous lesions; they are frequently multiple and occur in exposed areas such as the face, scalp and upper limbs. Since 5-20% of these lesions will become SCCs in 10 to 25 years, and there is no way to tell which lesions will become malignant, it is necessary to treat all AKs.10,11
Tarstedt and colleagues demonstrated that one PDT-MAL session (repeated after 3 months if the lesions persisted), was as effective as the initial treatment plan of two sessions with a oneweek interval.12 Facial AKs respond better to PDT-MAL due to the lower hyperkeratosis that they present compared to similar lesions when located in the acral segments. The use of PDTMAL is limited by the sensitivity to pain, which is directly proportional to the following patient characteristics: male gender, location on bald men''''''''s scalps, frontal region in both genders and multiple and extensive lesions on the face. 9 Due to such factors, we chose to carry out one session on each side of the face, with a one-week interval, in addition to taking several measures (discussed above) to minimize pain.9
Other many times minimized however fundamental aspects in the PDT-MAL for facial AKs,would be: the curettage of the larger and more hyperkeratotic lesions with the application of a thick layer of medication after compression with gauze, with the subsequent preparation of the occlusive curative with transparent PVC plastic film, carefully applied on the area to be treated in order to avoid removing the MAL applied to the lesions.
We verified a complete response to PDT-MAL from practically all patients with facial AK, with only six cases undergoing a new session after 12 weeks. One of the patients who presented only a partial resolution of AKs after the initial treatment had many lesions disseminated throughout the face; the others presented extensive lesions. Nevertheless, all presented great improvement and tolerance to the treatment, and were satisfied with a partial response.
Even though we obtained a good response to the treatment of AKs located in the dorsum, cervical region, and upper and lower limbs, this procedure’s high cost does not seem justified for treating those locations compared to the results obtained with conventional treatments. Therefore, PDT-MAL seems to be a more appropriate method for facial AKs in patients who have already had other treatments such as 5-fluorouracil and cryotherapy, as much for the high clinical response (around 90% in the literature 12,13,14) as for the photorejuvenation provided.
The pain during the 8 minutes of the session can be a limiting factor.We believe that performing the treatment in two stages (right and left sides of the face, with a one-week interval), in addition to taking measures to relieve the pain and having a good physician-patient relationship, can alleviate this side effect.9 In our study sample, erythema and edema did not cause significant discomfort, except in two patients (one of them developed pustules). In these cases, the problem was solved with the use of emollients and corticosteroid creams.
BD lesions constitute in situ SCC and typically occur in senior patients’ lower limbs (though they can occur in any cutaneous region), with around 3% of such lesions evolving into SCCs 15, of which 1/3 metastasize.16 Despite the fact that PDTMAL for BD is still used "off-label" in Brazil, it has been approved in 22 European Union countries. In a multicentric study with 2 PDT-MAL sessions administered in 7 days in cases of BD, the initial cure rate was 93%17. In a 12-month followup, the recurrence rate under PDT-MAL was 15%, compared to 21% for cryotherapy and 17% for 5-Fluouracil. 17
In the present study, 2 sessions of PDT-MAL were carried out to treat 11 lesions in patients aged 51-96 – most of them elderly and with co-morbidities. All lesions were located in the upper and lower limbs and dorsum, areas that are difficult to heal. After the end of treatment, in a follow-up that varied from six to twelve months, only two patients with lesions located in the dorsum did not present a histological cure after 12 weeks. One possible explanation is that the second session was carried out only 14 days after the initial session, since the patients were absent on the day scheduled for the treatment.
BCC lesions are the most common cutaneous neoplasias. They can be superficial (sBCC) or nodular (nBCC), pigmented or sclerodermiform. Primary BCCs located outside the “H” zone of the face can be classified as low risk, a circumstance in which both the aesthetic result and the antitumoral efficacy are important. In general, BCCs also affect a younger age group or occur as multiple lesions in tegument areas subjecting to dystrophic scars.
There is considerable evidence to support the use of PDTMAL in BCCs, including several phase III studies that demonstrate high histologically confirmed efficacy (80%) in 3 months for large or recurrent lesions, or those located in the H zone of the face. 18,19 In a four-year follow-up, the same studies verified a recurrence rate similar to that of cryotherapy (19%, versus 22% for PDT-MAL),20,21 with lower three-year recurrence rates (6%) for lesions with diameters equal to or smaller than 1 cm.20 Vinciullo and others22 and Horn and colleagues23 showed36- month recurrence rates of 15% and 31%, respectively, in lesions that were difficult to treat. In spite of the higher recurrence rate of lesions in the H zone of the face, PDT-MAL is effective in the treatment of BCCs, and is a viable alternative when surgery is contraindicated.
We used PDT-MAL in 18 BCC lesions, including a 37- year-old female patient with 2 lesions in the H zone of the face, who demonstrated a complete response with excellent aesthetic results (Figure 7). In that case, the choice of treatment was made after the explanation of the surgical option, which leads to a lower probability of reincidence.Nevertheless, as the patient presented 2 lesions, and multiple keratoses and solar melanoses, there was consensus on the choice for PDT-MAL.The patient was at the 12-month follow-up stage at the time this article was written.
The strongest evidence for the use of PDT-MAL in nBCC is based on 5 phase II studies; a total of 220 lesions were treated, with 73-94% efficacy.22-26 Horn and others 23 and Vinciullo and colleagues 22 showed a response rate between 94% and 87%, respectively. Lower rates can occur due to differences in the preparation of the lesion, as explained in the beginning of this article.A recurrence rate of 14% in 3 or 5 years after treatment was verified in a phase III study for nBCC,26 while for difficult lesions, the rate varied between 18 and 30% in 48- 60 months.22,23 In a retrospective study, the recurrence rate varied between 7% and 14% for thin and thick lesions, respectively,27 also demonstrating the importance of the preparation of the lesion.
Twelve nBCC lesions underwent PDT-MAL, with the clinical response confirmed by histological cure in all cases, at the Centro de Dermatologia Dona Libânia. In our casuistry, we also carried out 2 PDT-MAL sessions in two patients with Gorlin syndrome who presented pigmented nBCC in the retroauricular areas, however the lesions still persisted after 12 weeks, illustrating the difficulty in treating lesions with pigment.
PDT-MAL is an effective treatment for AK and NCNM, presenting efficacy and recurrence rates similar to those of conventional therapies, however with higher reincidence than that of surgery in nBCC and sBCC cases. Nevertheless, this method presents the best aesthetic result, and becomes an attractive option for sBCC and nBCC that occur outside of the H zone of the face and in areas of poor healing and lower probability of reincidence, such as the trunk and limbs. Likewise, because of the photorejuvenation entailed by the treatment, it becomes a first line method for facial AKs – especially multiple AKs – in patients with low phototypes or who have already tried lowercost treatments such as 5-fluorouracil and cryotherapy and have experienced a recurrence of the lesions.
An important limiting factor in the patients’ choice for PDT-MAL is the cost of the procedure. In this manner, it is the dermatologist’s duty to adequately position the method in terms of efficacy and reincidence, as compared to other options. It is important to emphasize the lower probability of reincidence with surgical treatment in sBCC and nBCC cases, especially in the H zone of the face, in infiltrated or hyperkeratotic lesions.
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