Actinic (solar) keratoses (AK) are epithelial, noninfiltrative, premalignant lesions caused by prolonged exposure to ultraviolet (UV) radiation (Marks, 1997). Clinically, AK lesions are described as small, dry, rarely pigmented, erythematous, scale-covered lesions, which are distributed on sun-exposed areas such as the face, bald scalp, neck, chest, back of the hands, and forearms (Goldberg & Mamelak, 2010). The etiology of AK is multifactorial, and risk factors include increased age, male gender, a fair skin phototype, and chronic sun exposure.
AK lesions are a concern worldwide with a prevalence of approximately 13% among Caucasian populations in Brazil (Sociedade Brasileira de Dermatologia, 2006), 15% in men in England (Memon, Tomenson, Bothwell, & Friedmann, 2000), 16%–25% in the United States (Rosen & Lebwohl, 2013), and up to 60% in Australia (Frost & Green, 1994). These lesions have the potential to progress into squamous cell carcinoma (SCC), and therefore, use of appropriate therapies is critical for effective treatment (Holmes, Foley, Freeman, & Chong, 2007).
Treatment options for AK include destructive therapies (cryosurgery and excisional surgery) and topical therapies (5-fluorouracil, imiquimod, diclofenac, and ingenol mebutate) (Fenske, Spencer, & Adam, 2010). However, many of these treatments are associated with treatment pain/discomfort and residual scarring leading to low patient satisfaction.
Conventional photodynamic therapy (c-PDT) with photosensitizing agents such as 5-aminolevulinic acid or methyl aminolevulinate (MAL) is an effective treatment for AK, particularly for the treatment of large areas of field change (Stockfleth et al., 2008 ; Wan & Lin, 2014). The procedure involves the topical application of a photosensitizer cream such as MAL for 3 hours, which results in the formation and accumulation of photoreactive protoporphyrin IX (PpIX) specifically in neoplastic tissue. PpIX is then activated by illumination using a red light-emitting diode lamp leading to formation of cytotoxic reactive oxygen species and, consequently, destruction of the targeted cells by apoptosis or necrosis (Lehmann, 2007). Although c-PDT is efficacious, it is associated with treatment-related pain and adverse events (burning and stinging) as well as a long incubation time (3 hours), which can be inconvenient for patients and clinical staff. Treatment-related pain may affect patient compliance. In addition, the need for specialized illumination equipment may limit availability of treatment and increase cost.
Daylight-mediated PDT (DL-PDT) with MAL cream is a convenient new option for AK using visible light as the light source for activation of PpIX, thereby eliminating the requirement for illumination equipment and prolonged in-clinic times. Upon its formation, PpIX is immediately photobleached by daylight, leading to targeted cell necrosis. The absence of PpIX accumulation because of its continuous activation can reduce treatment-related pain. In three Scandinavian clinical studies, DL-PDT showed similar efficacy to c-PDT, with high total lesion response rates (>70%) and less treatment-related pain (Wiegell et al., 2008, 2011 ; Wiegell, Haedersdal, Eriksen, & Wulf, 2009). A recent clinical study conducted in Australia including 100 patients with AK on the face/scalp showed that DL-PDT was not inferior to c-PDT in terms of complete lesion response (89.2% vs. 92.8%, respectively; 95% CI [−0.8, −0.3]), with a high maintenance rate at 6-month follow-up, better tolerated (treatment-related adverse events: 39% vs. 59%, respectively), nearly painless, and more convenient for patients (Rubel et al., 2014). In addition, this study showed that treatment efficacy was similar under all weather conditions except rain (See et al., 2015).
Results from a recent Phase III study (conducted in Northern and Southern European countries) corroborate the findings of the Australian study, with a single DL-PDT session being noninferior to c-PDT at 12 weeks in terms of AK Grade I and II lesion response rates and very low frequency of patient-reported pain with DL-PDT (Lacour et al., 2015).
Optimization of clinical practice is critical for the safe and effective treatment of AK lesions, and therefore, appropriate training of treating nurses is necessary. The objective of this article is to explain the practicalities and principles of DL-PDT to ensure best practice and its execution are appropriately undertaken by treating nurses. Moreover, this article aims to expand the armamentarium of the therapist in the management of AK where c-PDT is not available.
CLINICAL PRACTICE FOR DL-PDT
DL-PDT may be used for treatment of Grade I–II, thin nonhyperkeratotic AK lesions on the face and scalp as well as for patients with large areas of actinic damage (See et al., 2015 ; Stockfleth et al., 2008). DL-PDT is not recommended for Grade III (hyperkeratotic lesions), although pretreatment with curettage or other modalities such as keratolytics (e.g., urea, lactic acid, or salicylic acid creams) to reduce hyperkeratosis may be considered.
Treatment Period and Weather Conditions
Recent analyses of meteorological data from Australia (eight geographical locations) concluded that DL-PDT for the treatment of face and scalp AK can be performed effectively throughout the year as long as weather conditions permit daylight exposure and allow patients to remain under direct light for 2 hours (Spelman et al., 2016). In Europe, according to latitudes, optimal light intensity for DL-PDT is achieved throughout the year at 37°–43°, from February to October at 45°–48°, and from March to October at 51°–55°. At higher latitudes (≥60°), although light intensity is optimal from March to September, DL-PDT should not be performed before May because of low temperatures (data on file). Patients may not consent to 2 hours of outdoor exposure under cold temperatures. In addition, the production of PpIX may be lowered at cold temperatures (Juzeniene, Juzenas, Kaalhus, Iani, & Moan, 2002 ; Wiegell et al., 2013). Treatment during rainy weather is not recommended as there are no data to support treatment efficacy under these conditions.
Physicians or nurses should explain to patients the rationale of DL-PDT, the differences between visible light and UV light, and the need for use of a chemical sunscreen to prevent skin damage caused by UV radiation. Use of chemical sunscreen will not prevent visible light from penetrating and activating PpIX in the skin. In contrast, use of physical filters (e.g., zinc oxide, iron oxide, titanium dioxide, or color tints) may block visible light and therefore must be avoided. Patients should also be informed of the potential for skin reactions (e.g., erythema, desquamation, swelling, crusting, and scaling) associated with DL-PDT. These reactions are expected to peak in intensity during the first 2–3 days after treatment and resolve spontaneously within 2 weeks after treatment.
Lesion Preparation and Treatment Application
Skin preparation before DL-PDT may enhance the penetration of MAL cream into the treatment area and contribute to improved cosmetic outcomes (Szeimies et al., 2013). First, nurses should confirm the treatment area with the treating physician/dermatologist and prepare all required DL-PDT application equipment. The treatment area must be washed with normal saline before sunscreen application. Nontinted, nonphysical blocker sunscreen of SPF 30 or higher should be applied to the entire sun-exposed area, including the DL-PDT treatment area to protect the skin during the 2-hour exposure to daylight. Sunscreen should be applied 10 minutes before application of MAL cream. The scale over larger AK lesions should be removed with gauze or a curette. After skin preparation, a thin, even layer of MAL cream should be applied to the lesion and surrounding area of normal skin (5- to 10-mm border) or to the entire area of actinic damage to treat subclinical lesions. This should be applied using a spatula or by hand, using disposable gloves. The treated area is not to be occluded if on exposed sites. However, where the treated area is under clothing or the cream is likely to be rubbed off while traveling before exposure, a transparent medical dressing should be used to prevent the cream being inadvertently wiped off. According to recent consensus recommendations on the use of DL-PDT, 1–2 grams of MAL cream is sufficient to treat a full face (See et al., 2015).
Procedure: MAL Cream Activation
Daylight exposure should commence within 30 minutes after application of MAL cream. Clinical data have shown that the degree of pain was associated with the delay (when greater than 30 minutes) from application of MAL cream to daylight exposure (Wiegell et al., 2009). Patients may take advantage of the initial 30 minutes to return home and expose the treated area to daylight in their garden or balcony. The transparent medical dressing (if in place in case of lesions present in covered areas) should be removed, and the DL-PDT area should be exposed to daylight for 2 hours. All other areas exposed to sunlight should be protected (sunscreen, clothing, hat, sunglasses, etc.). Patients are to remain outdoors and avoid activities that may result in perspiration. If necessary, patients who are uncomfortable may take shelter intermittently in a covered outdoor area. However, they should avoid areas of deep shade where there is a lack of diffuse light.
Daylight exposure for 2 hours is essential, and reduced exposure time may result in reduced treatment efficacy. Exposure longer than 2 hours is not recommended because of the increased risk of inflammation (e.g., increased risk of sunburn). Moreover, there is no evidence to support that longer exposure times will result in greater efficacy (Wiegell et al., 2011). In case of rainfall during daylight exposure, the patient is advised to take shelter under a covered roof and try to complete the 2-hour exposure. If this is not possible, the treatment should be repeated.
Completion of Treatment and Patient Follow-Up
After daylight exposure is complete, any residual MAL cream should be washed off, and the standard PDT postprocedure protocol (i.e., application of bland emollient twice daily and sun protection) should be followed.
Patients should be advised to protect the treated areas from further sun exposure on the treatment day and apply a bland moisturizer at night to hydrate the skin for up to 1 week after treatment. Patients should be followed up, evaluated, and treated for any residual AK lesions, according to usual clinical practice. In cases where one DL-PDT treatment does not completely clear the lesions, a retreatment with DL-PDT is considered usually at the 3-month follow-up visit. Patients should be kept under follow-up even if the lesions are clear as per usual clinical practice. Figures 1, 2 and 3 show patients before and after treatment with DL-PDT.
Table 1 provides important tips for DL-PDT. DL-PDT is a simple and convenient option for the safe and effective treatment of Grade I and II AK lesions on the face and scalp, allowing treatment of large areas of actinic damage with reduced in-clinic times and little or no pain. AK lesions have the potential to progress into SCC, and therefore, use of appropriate therapies and optimization of clinical practice are critical for safe and effective treatment. Nurses play a key role in ensuring best clinical practice and effective treatment.
Fenske N. A., Spencer J., Adam F. (2010). Actinic keratoses: Past, present and future. Journal of Drugs in Dermatology
, 9(5), s45–s49.
Frost C. A., Green A. C. (1994). Epidemiology of solar keratoses. The British Journal of Dermatology
, 131(4), 455–464.
Goldberg L. H., Mamelak A. J. (2010). Review of actinic keratosis. Part I: Etiology, epidemiology and clinical presentation. Journal of Drugs in Dermatology
, 9(9), 1125–1132.
Holmes C., Foley P., Freeman M., Chong A. H. (2007). Solar keratosis: Epidemiology, pathogenesis, presentation and treatment. The Australasian Journal of Dermatology
, 48(2), 67–74.
Juzeniene A., Juzenas P., Kaalhus O., Iani V., Moan J. (2002). Temperature effect on accumulation of protoporphyrin IX after topical application of 5-aminolevulinic acid and its methylester and hexylester derivatives in normal mouse skin. Photochemistry and Photobiology
, 76(4), 452–456.
Lacour J. P., Ulrich C., Gilaberte Y., Von Felbert V., Basset-Seguin N., Dreno B., Szeimies R. M. (2015). Daylight photodynamic therapy with methyl aminolevulinate
cream is effective and nearly painless in treating actinic keratoses: A randomised, investigator-blinded, controlled, phase III study throughout Europe. Journal of the European Academy of Dermatology and Venereology
, 29(12), 2342–2348.
Lehmann P. (2007). Methyl aminolaevulinate-photodynamic therapy: A review of clinical trials in the treatment of actinic keratoses and nonmelanoma skin cancer. The British Journal of Dermatology
, 156(5), 793–801.
Marks R. (1997). Epidemiology of non-melanoma skin cancer and solar keratoses in Australia: A tale of self-immolation in Elysian fields. The Australasian Journal of Dermatology
, 38, S26–S29.
Memon A. A., Tomenson J. A., Bothwell J., Friedmann P. S. (2000). Prevalence of solar damage and actinic keratosis in a Merseyside population. The British Journal of Dermatology
, 142(6), 1154–1159.
Rosen T., Lebwohl M. G. (2013). Prevalence and awareness of actinic keratosis: Barriers and opportunities. Journal of the American Academy of Dermatology
, 68, S2–S9.
Rubel D. M., Spelman L., Murrell D. F., See J. A., Hewitt D., Foley P., Shumack S. (2014). Daylight photodynamic therapy with methyl aminolevulinate
cream as a convenient, similarly effective, nearly painless alternative to conventional photodynamic therapy in actinic keratosis treatment: A randomized controlled trial. The British Journal of Dermatology
, 171(5), 1164–1171.
See J. A., Shumack S., Murrell D. F., Rubel D. M., Fernández-Peñas P., Salmon R., Spelman L. (2015). Consensus recommendations on the use of daylight photodynamic therapy with methyl aminolevulinate
cream for actinic keratoses in Australia. The Australasian Journal of Dermatology
Sociedade Brasileira de Dermatologia. (2006). Data analysis of the Brazilian Society of Dermatology skin cancer prevention campaign, 1999 to 2005. Anais Brasileiros de Dermatologia
, 81, 529–535.
Spelman L., Rubel D. M., Murrell D. F., See J. A., Hewitt D., Foley P., Fernandez-Penas P. (2016). Treatment of face and scalp solar (actinic) keratosis with daylight-mediated photodynamic therapy
is possible throughout the year in Australia: Evidence from a clinical and meteorological study. The Australasian Journal of Dermatology
, 57, 24–28. doi:10.1111/ajd.12295
Stockfleth E., Ferrandiz C., Grob J. J., Leigh I., Pehamberger H., Kerl H., & European Skin Academy. (2008). Development of a treatment algorithm for actinic keratoses: A European Consensus. European Journal of Dermatology
, 18(6), 651–659.
Szeimies R. M., Lischner S., Philipp-Dormston W., Walker T., Hiepe-Wegener D., Feise K., Karrer S. (2013). Photodynamic therapy for skin rejuvenation: Treatment options—Results of a consensus conference of an expert group for aesthetic photodynamic therapy. Journal der Deutschen Dermatologischen Gesellschaft
, 11(7), 632–636.
Wan M. T., Lin J. Y. (2014). Current evidence and applications of photodynamic therapy in dermatology. Clinical, Cosmetic and Investigational Dermatology
, 7, 145–163.
Wiegell S. R., Fabricius S., Heydenreich J., Enk C. D., Rosso S., Bäumler W., Wulf H. C. (2013). Weather conditions and daylight-mediated photodynamic therapy
: Protoporphyrin IX-weighted daylight doses measured in six geographical locations. The British Journal of Dermatology
, 168(1), 186–191.
Wiegell S. R., Fabricius S., Stender I. M., Berne B., Kroon S., Andersen B. L., Wulf H. C. (2011). A randomized, multicentre study of directed daylight exposure times of 1½ vs. 2½ h in daylight-mediated photodynamic therapy
with methyl aminolaevulinate in patients with multiple thin actinic keratoses of the face and scalp. The British Journal of Dermatology
, 164(5), 1083–1090.
Wiegell S. R., Haedersdal M., Eriksen P., Wulf H. C. (2009). Photodynamic therapy of actinic keratoses with 8% and 16% methyl aminolaevulinate and home-based daylight exposure: A double-blinded randomized clinical trial. The British Journal of Dermatology
, 160(6), 1308–1314.
Wiegell S. R., Haedersdal M., Philipsen P. A., Eriksen P., Enk C. D., Wulf H. C. (2008). Continuous activation of PpIX by daylight is as effective as and less painful than conventional photodynamic therapy for actinic keratoses; a randomized, controlled, single-blinded study. The British Journal of Dermatology
, 158(4), 740–746.