INTRODUCTION — Photodynamic therapy (PDT) is a two-step treatment in which a drug that acts as a photosensitizer is administered to specifically target a diseased tissue of interest, followed by illumination with visible light to activate the drug and destroy the target tissue [1]. PDT was developed primarily for treatment of cancer and precancers. While PDT has been used to treat internal cancers in many parts of the body by administering a systemic photosensitizer and delivering light through an optical fiber, by far the most common application of PDT in clinical medicine is for treatment of cancer and precancer of the skin [2].
This topic will review the principles and practical applications of PDT for treating neoplastic and preneoplastic conditions of the skin. The use of PDT in oncology and internal medicine is discussed in specific topic reviews.
●(See "Management of superficial esophageal cancer".)
●(See "Endobronchial photodynamic therapy in the management of airway disease in adults".)
PRINCIPLES AND MECHANISMS — Nearly all drugs used for PDT are derivatives of heme (porphyrins), large tetrapyrrole molecules produced in the mitochondria of all cells. Porphyrins are products of a well-known biochemical pathway, catalyzed by eight enzymes that can be genetically disrupted in the various forms of hereditary porphyria (figure 1). Thus, PDT can be considered a form of "artificial porphyria." (See "Porphyrias: An overview".)
Because porphyrins are conjugated (containing multiple double bonds), they can absorb visible wavelengths of light very efficiently and convert the energy into chemical reactions [1]. Historically, the earliest PDT drugs for medical use were derived from hemoglobin (eg, hematoporphyrin derivative, benzoporphyrin derivative) and other compounds with structural similarities to heme [3]. However, in dermatology, the use of such preformed photosensitizers has been largely replaced by prodrugs that represent the second step in the porphyrin synthesis pathway, namely 5-aminolevulinic acid (ALA) or an esterified form, methyl aminolevulinate (MAL) (figure 2A-B).
ALA or MAL are applied topically, taken up by neoplastic cells, and converted into various porphyrins; protoporphyrin IX (PPIX) is the form that absorbs light most efficiently. This approach to PDT works because ALA bypasses the first (inhibitory) feedback step in the heme synthesis pathway, thus allowing PPIX to accumulate to very high levels (figure 2A) [4].
Most uses of PDT involve the topical application of ALA or MAL to the skin for several hours to allow the buildup of PPIX within target cancer or precancer cells, followed by illumination with a prescribed amount of light (delivered from an approved broadband lamp or a laser) to activate the PPIX. The photoactivation of PPIX, in the presence of oxygen, causes free radical-based photochemical reactions within mitochondria and surrounding membranes, ultimately leading to the death of the target cells. To achieve good photoactivation, the chosen light source must emit sufficient energy at wavelengths that correspond to major peaks in the absorption spectrum of PPIX. Typically, 400 nm (blue) or 635 nm (red) are chosen (figure 2B).
CELLULAR EFFECTS OF PHOTODYNAMIC THERAPY — Perhaps the most important principle in PDT is its high selectivity for neoplastic cells and tissues. Even when the prodrug is applied over a very broad area of skin, cancerous or precancerous cells accumulate far more protoporphyrin IX (PPIX) than do normal epidermal cells for two reasons:
●Higher rates of aminolevulinic acid uptake
●Higher rates of synthesis and accumulation of PPIX within the mitochondria
Reasons for the last include tumor-selective changes in expression and/or activity of critical enzymes within the heme synthesis pathway [5]. The selective PPIX accumulation in tumor tissue in vivo, relative to surrounding normal skin, has been clearly demonstrated using animal models of squamous cell carcinoma [6], squamous precarcinoma [7], and basal cell carcinoma [8], as well as by noninvasive PPIX measurements in human actinic keratoses [9]. Upon illumination, the consequence of the selectively higher target PPIX levels is preferential photodestruction of the cancer tissue relative to neighboring normal skin cells [10].
Early research in PDT focused on the physical and biochemical mechanisms by which PDT kills cancer cells, with an assumption that high intracellular PPIX levels and a high light intensity (fluence rate) are necessary for good tumor killing [3]. However, in vivo investigations and clinical experience show that both lower PPIX and light intensities also work quite well, suggesting that previously unrecognized mechanisms as well as the participation of the immune system may be critical for generating a therapeutic response to PDT. (See 'Variations on the standard photodynamic therapy regimen' below.)
One important consequence of the mitochondrial membrane-targeted mechanism by which PDT kills neoplastic cells is that PDT is nonmutagenic. This gives PDT a distinct advantage over DNA-targeting modalities because, unlike ionizing radiation or many chemotherapeutic agents, PDT can be performed multiple times without fear of introducing oncogenic DNA mutations. Another advantage of PDT is the fact that treated lesions heal without a scar, perhaps due to suppressive effects upon fibroblasts [11,12]. Thus, PDT should be considered a nonscarring treatment option for patients who develop frequent nonmelanoma skin cancers and precancers.
LIGHT SOURCES — The types of visible light that can be used for PDT of the skin are surprisingly varied and include various coherent light sources (lasers and light-emitting diodes), incoherent sources (broadband lamps), and natural sunlight (see 'Variations on the standard photodynamic therapy regimen' below). However, efficacy and safety are critical in PDT, and therefore, only validated light sources can be recommended. In the United States, two broadband light sources that target the major absorption peaks of protoporphyrin IX (figure 2B) are approved by the US Food and Drug Administration (FDA):
●A blue light source (BLU-U Blue Light Photodynamic Therapy Illuminator 400 nm), to be used with the proprietary aminolevulinic acid (ALA) 20% solution (Levulan Kerastick)
●A red light source (BF-RhodoLED 635 nm), to be used with the proprietary ALA 10% nanoemulsion (Ameluz)
These light sources should be used exclusively with the companion prodrug for which the drug/light combination was tested in the original clinical trials [13,14].
Although clinicians may use other light sources, the results are not always predictable. Importantly, medical insurance companies often will not reimburse for treatment sessions with drugs or light sources that were not FDA approved.
TOPICAL PHOTOSENSITIZING MEDICATIONS — Two drug/light combinations are approved by the US Food and Drug Administration (FDA) for treatment of nonhyperkeratotic actinic keratosis (AK) of the face and scalp:
●Aminolevulinic acid (ALA) 20% solution (Levulan Kerastick), a liquid that is allowed to dry on the skin and is then activated using the proprietary blue light source (BLU-U 400 nm) [13]. This drug/light combination is widely available in the United States but not in Europe or Canada.
●ALA 10% nanoemulsion (Ameluz), a gel that must be covered with an occlusive dressing and later activated using the proprietary red light (BF-RhodoLED 635 nm) [14].
In 2018, ALA 20% solution (Levulan Kerastick) has also been approved by the US FDA for the treatment of AKs of the upper extremities [15].
The ALA 10% nanoemulsion was developed in Europe, where it is approved for PDT in combination with red light for the treatment of mild and moderate AK.
Another agent, methyl aminolevulinate (MAL) 16.8% cream (Metvix) used with red light, is available in Europe, Canada, Australia, and other countries, but not in the United States, for the treatment of nonhyperkeratotic AK, superficial and nodular basal cell carcinoma, and squamous cell carcinoma in situ [16]. However, the approval may vary among countries.
CLINICAL INDICATIONS
Approved indications — PDT is approved by the US Food and Drug Administration (FDA) for the treatment of thin, nonhyperkeratotic actinic keratosis (AK) [17]. In Europe [16], Canada, Australia, and other countries worldwide, PDT is also approved by the local regulatory authorities for the treatment of superficial and thin nodular basal cell carcinoma (BCC), when other available therapies are not acceptable (either due to possible morbidity or poor cosmetic outcome), and squamous cell carcinoma (SCC) in situ (Bowen disease). However, the approval may vary among countries.
●Actinic keratosis – In an earlier phase III trial of 20% aminolevulinic acid (ALA) solution incubated for 14 to 18 hours without occlusion in conjunction with blue light, 73 percent of subjects had 100 percent AK clearance at 12 weeks [13]. Shorter incubation times are used in clinical practice, based upon a series of studies showing similar efficacy despite this modification [9,18,19]. In the European phase III trial of 10% ALA nanoemulsion gel incubated for three hours after removal of scales/crusts and occlusion, in conjunction with red light, 91 percent of subjects had 100 percent AK clearance at 12 weeks [14]. The efficacy of PDT for the treatment of AK has been confirmed by multiple randomized trials and two meta-analyses [20,21]. (See "Treatment of actinic keratosis", section on 'Photodynamic therapy'.)
●Basal cell carcinoma – Superficial BCC lesions appear to be most responsive to therapy, with sustained response rates ranging from 72 to 97 percent [22-27]. Nodular BCCs are less likely than superficial BCCs to respond to treatment with PDT, with sustained response rates of 33 to 76 percent [22,28-30]. (See "Treatment and prognosis of basal cell carcinoma at low risk of recurrence", section on 'Photodynamic therapy'.)
Given the numerous BCCs that arise in patients with basal cell nevus syndrome, efforts are being made to optimize PDT so that it can be used as a noninvasive treatment option for both children and adults with this genetic disease [31-36]. (See "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)".)
●Squamous cell carcinoma in situ (Bowen disease) – In patients with SCC in situ, studies have demonstrated initial clearance rates of 88 to 100 percent at three months and sustained clearance of 68 to 89 percent at one and a half to four years after one to two cycles of methyl aminolevulinate (MAL)-PDT [37-40]. A randomized study comparing MAL-PDT with placebo-PDT, cryotherapy, or topical 5-fluoruracil (5-FU) for the treatment of SCC in situ found that MAL-PDT was superior in efficacy to 5-FU and placebo-PDT and was less painful than cryotherapy [37]. After a single session of ALA-PDT, only 53 percent of patients were reported to still be clear at five years [41]. Therefore, repeated sessions and monitoring should be considered as part of the treatment plan. PDT is not recommended for invasive SCCs due to poor clearance rates and metastatic potential [39,42].
Off-label use — PDT has been increasingly used off label for the treatment of a variety of neoplastic and non-neoplastic skin conditions. Examples include:
●Acne vulgaris – The use of blue light alone, without a topical photosensitizer, is FDA approved for the treatment of moderate inflammatory acne vulgaris [43]. Propionibacterium acnes produce porphyrins as part of their normal metabolism, which allows a direct photodynamic effect. ALA application prior to illumination with blue or red light has been reported to improve outcomes [44-48]. The duration of acne remission after PDT appears to be extended with longer incubation times (at least three hours) and the use of red light [49]. (See "Light-based, adjunctive, and other therapies for acne vulgaris".)
●Photorejuvenation – In addition to AK clearance on photodamaged skin, PDT also exerts photorejuvenating effects [50]. It can lessen the appearance of fine lines and uneven skin tone, as well as improve skin texture. Intense pulsed light devices are most commonly used in combination with topical ALA for this cosmetic treatment [51-53]. (See "Nonablative skin resurfacing for skin rejuvenation", section on 'Photodynamic therapy'.)
Other off-label indications are summarized in the table (table 1).
STANDARD PHOTODYNAMIC THERAPY REGIMENS FOR ACTINIC KERATOSES — PDT protocols vary depending on the photosensitizer used. Modifications may be needed to enhance the therapeutic response. (See 'Variations on the standard photodynamic therapy regimen' below.)
Before initiating treatment — Prior to initiating treatment with PDT, it is important to review the patient's medical history, educate the patient on appropriate post-treatment care, and obtain an informed consent:
●Review the patient's medical history, medication list, and allergies to ensure no contraindications to PDT (see 'Contraindications to photodynamic therapy' below). Ask whether the patient has a history of recurrent herpes labialis and consider providing antiviral prophylaxis.
●Confirm that the patient understands the requirement to avoid sunlight and bright indoor lights for 48 hours after the procedure and explain the "sunburn-like" appearance of the skin expected for several days after treatment.
●Obtain verbal or written informed consent to proceed with the treatment.
Photodynamic therapy administration — The administration of PDT involves the following steps:
●Degrease the skin to be treated with an ethanol or acetone pad.
●If using aminolevulinic acid (ALA) 10% nanoemulsion, scales will need to be gently removed prior to gel application. Avoid the induction of bleeding.
●When applying the topical photosensitizing drug, wear nitrile gloves. Adequate protection is not provided by vinyl and latex gloves.
●Apply topical photosensitizer to individual skin lesions or to an area of skin (if field therapy is desired). Refer to package insert for specific application instructions for each product (such as desired thickness of gel or maximum amount of product to be used during a treatment session) [54,55].
●If necessary, cover with an occlusive, nonabsorbent dressing. Occlusion is not required when using ALA 20% solution on face or scalp but is used when using topical ALA 10% nanoemulsion. Occlusion is indicated when using ALA 20% solution on upper extremities [15].
●Incubation time when using ALA 20% solution typically varies from zero to six hours and is determined by the treating clinician. In the US Food and Drug Administration (FDA) prescribing information, the incubation times for ALA 20% solution are 14 to 18 hours for scalp or face and 3 hours for upper extremities, with occlusion. ALA 10% nanoemulsion incubation time is three hours.
●If a gel is used, it must be wiped away with saline and gauze prior to illumination.
●Have the patient sit comfortably in a chair or recline on an exam table in preparation for illumination.
●Position lamp over treatment area, approximately two to four inches from the skin. Reference package insert [43,56].
●During illumination, the patient and provider must wear appropriate eye protection. The patient should not stare into the light and may be most comfortable with their eyes closed.
●Standard total light dose delivered when using ALA 20% solution with blue light (417±5 nm) is 10 J/cm2, which requires 16 minutes and 40 seconds of illumination time with the BLU-U Blue Light Photodynamic Therapy Illuminator 400 nm light source [43]. The dose when using ALA 10% nanoemulsion with red light (635±9 nm) is 37 J/cm2, which takes approximately eight minutes with the BF-RhodoLED 635 nm light source [56]. (See 'Light sources' above.)
●The light operator should stay with the patient during illumination to assist with any pain-relieving measures required during the treatment. (See 'Pain control measures' below.)
●Gently wash off treatment area at the end of the session and apply a physical sunscreen.
●Review and provide written aftercare instructions. Optional prescriptions include:
•Short course of oral antiviral agent for herpes labialis prophylaxis in patients with history of recurrent herpes simplex virus.
•Small quantity of low-to-medium strength topical steroid ointment (table 2) for application during first few days post-treatment to help reduce pain and inflammation.
●Depending on the severity of the actinic keratosis (AK), a second session may be scheduled in four to eight weeks. Otherwise, a follow-up visit in three months is recommended to assess AK clearance.
VARIATIONS ON THE STANDARD PHOTODYNAMIC THERAPY REGIMEN — Since the first US Food and Drug Administration (FDA) approval of a PDT regimen for actinic keratoses (AKs) in 1999, many studies have focused on improving the efficacy of PDT and reducing the inflammatory side effects. Such efforts have included measures to increase prodrug uptake, improve protoporphyrin IX (PPIX) accumulation, and reduce the pain that patients experience during illumination. (See 'Pain control measures' below.)
Modifications to increase drug uptake
●Curettage – The gentle removal of scales and crust on AK lesions is recommended in the protocol for aminolevulinic acid (ALA) 10% nanoemulsion and for methyl aminolevulinate (MAL) in Europe and Canada [55,57]. For AK lesions on the scalp, abrading the lesions with fine sandpaper prior to application of ALA 20% solution followed by blue light improves the AK lesion clearance rate by an average of 55 percent [58].
●Microneedling – The use of a roller with microneedles can improve prodrug uptake and clinical response and reduce the incubation time [59-62].
●Fractional lasers – The use of an ablative fractional laser can increase ALA or MAL penetration and improve the efficacy of PDT [63,64]. A study evaluating the effects of curettage, microneedling, microdermabrasion, and laser ablation prior to PDT found a significant increase in intraepidermal PPIX accumulation after each intervention compared with no pretreatment [65]. (See "Principles of laser and intense pulsed light for cutaneous lesions", section on 'Ablative'.)
●Occlusion – An occlusive dressing, to increase drug penetration prior to illumination, has been shown to increase AK clearance rates, whether the prodrug is 5-ALA 20% liquid [66], ALA 10% nanoemulsion [14], or MAL 16.8% cream [18,67].
●Thermal effects – It has been shown that mild local hyperthermia (raising the skin temperature to 40 to 42°C) increases PPIX synthesis and enhances the therapeutic response of AK to PDT [68,69].
Modifications to increase protoporphyrin IX synthesis and accumulation — Long ALA incubation times are known to enhance PPIX accumulation, with maximal PPIX levels at 14 to 18 hours [54]. An iron chelator, such as deferoxamine, inhibits ferrochelatase (the last enzyme in the heme pathway) and thereby enhanced PPIX accumulation in animal and pilot human studies [70,71]. Other studies in animal models and small human studies have shown that pretreatment with several common drugs, including methotrexate [72], vitamin D [6], and topical fluorouracil [7,73], causes a prodifferentiation response in squamous cancer cells that enhances PPIX accumulation and improves PDT efficacy.
In a small split-body trial including 17 patients with AK, pretreatment of lesions on one side of the body with topical fluorouracil for six days prior to applying MAL cream increased the level of PPIX by two- to threefold, as well as p53 induction, compared with non-pretreated lesions [73]. Clearance rates after PDT with or without topical fluorouracil pretreatment were 75 versus 45 percent at three months and 67 versus 39 percent at six months, respectively.
In another study, it was shown that pretreatment with high-dose oral vitamin D taken at home for five days prior to blue light PDT with short or no incubation ("in-office painless PDT") significantly increases AK lesion clearance outcomes [74]. (See 'Pain relief during treatment' below.)
Recommendation about the use of these combination regimens must await the results of larger clinical trials.
Short-contact photodynamic therapy regimens — Because patients frequently experience stinging pain when light is administered after long PDT prodrug incubation times (eg, 14 to 18 hours after ALA 20% solution application), clinicians have tried shorter incubation times in an attempt to reduce this adverse effect. PPIX was shown to accumulate in the skin with linear kinetics, even during the first two-hour, post-ALA application [9], so many clinicians now routinely apply ALA 20% solution for a one-to-two-hour incubation period prior to blue light exposure. A study comparing ALA incubation times of one, two, or three hours found very similar therapeutic efficacy with all three conditions [18]. Other reports have used even shorter incubation times but with a relatively long duration of light exposure. These "in-office painless PDT" regimens have proven effective for AK of the face and scalp [75-77]. (See 'Pain relief during treatment' below.)
Daylight photodynamic therapy — In 2008, a group of Danish investigators published a study showing that natural sunlight can be used to activate PPIX in AK lesions, a technique known as "daylight PDT" [78]. With this regimen, MAL is applied and then patients are sent outside in the sun for approximately two hours. Postillumination erythema and lesion clearance rates are similar to those seen with artificial light sources. Interestingly, patients experience very little pain with daylight PDT. Many subsequent trials have confirmed these findings [79]. While advantages of daylight PDT include low cost and reduced pain, exposure to ultraviolet B wavelengths may raise some concern. Also, the technique should be viewed with caution in parts of the world where solar irradiance is very intense, creating a potential safety issue. Although daylight PDT was originally developed using MAL, protocols employing ALA 20% solution have also been developed [80]. (See "Treatment of actinic keratosis", section on 'Daylight photodynamic therapy'.)
SAFETY MEASURES
Eye protection — Retinal damage from the visible light spectrum has been described and may play a role in age-related macular degeneration [81-83]. Therefore, appropriate goggles that block either blue or red light should be worn by the patient throughout illumination. The patient must be advised not to stare directly into the light. Likewise, it is recommended that any other individuals in the room during treatment wear protective eyewear.
Use of other photosensitizing agents — Although only visible light is used during PDT, an exacerbated reaction could possibly occur when a PDT patient is concurrently taking a medication known to be phototoxic in the setting of ultraviolet A light exposure [84]. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Drug-induced'.)
It is commonly recommended that tetracycline antibiotics be stopped one to two weeks prior to PDT, if possible. Retinoids should also be temporarily discontinued prior to PDT, as they can exacerbate post-PDT inflammatory reactions. Examples of other photosensitizing medications to consider stopping temporarily are thiazide diuretics, griseofulvin, phenothiazines, fluoroquinolones, St. John's wort, sulfonylureas, sulfonamides, and nonsteroidal anti-inflammatory drugs [55].
SHORT- AND LONG-TERM ADVERSE EFFECTS
●Temporary photosensitivity to light in areas to which the topical photosensitizer is applied is an expected and desired effect; this photosensitivity can remain up to 48 hours after the treatment, which is why total sun avoidance for 48 hours is mandatory.
●Transient, amnestic episodes have been reported during postmarketing use of aminolevulinic acid (ALA) 20% solution (Levulan Kerastick) in combination with BLU-U Blue Light Photodynamic Therapy Illuminator [85]. (See 'Topical photosensitizing medications' above and 'Light sources' above.)
●In addition to temporary pain (see 'Pain control measures' below), a localized, erythematous reaction can typically be expected for four to seven days and may be accompanied by a tingling or burning sensation, edema, minute vesicles, or crusting. After the erythematous reaction, the patient may experience exfoliation and pruritus of the skin for up to a week, which should be treated with soothing, bland emollients.
●Sterile pustule development has been described following PDT. If pustules are persistent, painful, or worsen when healing would be expected, consider testing for a possible Staphylococcus aureus or methicillin-resistant S. aureus superinfection [86,87]. This complication can sometimes arise in men who shave their faces with a contaminated razor or in immunosuppressed patients. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft tissue infections".)
●Flares of herpes labialis after PDT have been observed in patients with a history of recurrent cold sores. A prescription for a prophylactic antiviral (eg, valacyclovir 1 g/day for five days) may be considered for patients with frequent flares, especially when treating actinic cheilitis [88]. (See "Treatment and prevention of herpes simplex virus type 1 in immunocompetent adolescents and adults", section on 'Prophylaxis for recurrent HSV with identified trigger'.)
●Hypo- or hyperpigmentation is uncommon but can occur in darker skin types [86,89]. As with other types of postinflammatory hypo- or hyperpigmentation, it may take many weeks to resolve.
●Contact allergy is rare but can occur if the patient is allergic to the active or inactive ingredients in the topical photosensitizer. For ALA 10% nanoemulsion product, inactive ingredients include sodium benzoate, soybean phosphatidylcholine, and propylene glycol [55]. For ALA 20% solution, inactive ingredients include alcohol USP (ethanol content = 48 percent volume/volume), water, laureth-4, isopropyl alcohol, and polyethylene glycol [54].
●Scarring is rare. In fact, PDT has been used to improve the appearance of hypertrophic scars. The mechanism is thought to involve the inhibition of collagen synthesis and induction of matrix metalloproteinases [11,12].
PAIN CONTROL MEASURES — Pain associated with PDT is a short-term side effect, but it is one of the limiting factors in delivering this noninvasive therapy for skin disease [90]. Pain is experienced during illumination and/or post-treatment and can be intense for some patients. Research on the mechanism of pain during the illumination phase of PDT suggests that receptor channels (transient receptor potential ankyrin type 1 and transient receptor potential vanilloid type 1) may be involved. These channels are expressed in the nerve endings of pain fibers and become stimulated when protoporphyrin IX (PPIX), which accumulates in nearby cancer cells and then diffuses into nearby nerves, is activated by exposure to light [91].
Pain perception varies among individuals but is usually more severe when treating large treatment areas and/or highly photodamaged skin of the face or scalp [92,93]. Anecdotally, patients tend to experience more pain with red light than with blue light PDT, and lower pain scores have been seen with shorter wavelengths of light, such as green light, compared with red light [94,95]. It is debated whether methyl aminolevulinate (MAL) is less painful than aminolevulinic acid (ALA) [96-99].
Pain relief during treatment
●Distraction methods – Conversation or individualized music are often welcomed methods of distraction.
●Cooling – Cold air/mist/compresses have been reported to be one of the most effective ways to reduce, but not eliminate, the pain associated with PDT [90,100,101]. Unfortunately, cooling the treatment area may result in lower PPIX photobleaching and, hence, could negatively affect PDT outcome [102]. Therefore, cooling devices should be used briefly and only as needed.
●Topical anesthetics – No benefit was shown with the use of the following topical anesthetics for pain associated with PDT:
•EMLA (eutectic mixture of local anesthetics, containing 2.5% lidocaine and 2.5% prilocaine) [92,103]
•Lidocaine hydrochloride 3% cream [19]
•Tetracaine 4% gel [104]
●Locally infiltrative anesthetics – Local lidocaine injections, as well as tumescent anesthesia containing lidocaine, have been used to control the pain associated with MAL-PDT in the treatment of Gorlin syndrome [33]. Mepivacaine 1% injected intraorally has been used for the treatment of actinic cheilitis with PDT [106]. Successful pain control has also been reported with locally injected 0.5% lignocaine and adrenaline or a bupivacaine/adrenaline mixture [107]. Lidocaine has no adverse effect on ALA-PDT therapeutic outcomes, at least in vitro [108].
●Nerve block – Nerve blocks administered approximately 10 to 15 minutes prior to PDT reduce severe, intractable pain when treating extensive actinic keratoses (AKs) on the face and scalp without affecting the clinical outcome [109-112].
●Systemic analgesia – Significant pain reduction during PDT has been observed with the application of an inhaled nitrous oxide/oxygen mixture [113].
●Interrupted illumination – Delivering continuous light in two separate sessions with a three-minute intermission, in combination with cool water/pack application, has been shown to reduce PDT pain scores [114].
●Lower irradiance/daylight-mediated PDT – Although longer exposure times are required, daylight PDT is essentially painless [79]. (See 'Daylight photodynamic therapy' above.)
●Two-step irradiance – Pain can be minimized by administering red light at a low irradiance until the majority of PPIX is photobleached and then increasing to a higher irradiance until the total light dose is reached [115]. For example, an initial irradiance of 30 to 50 mW/cm2 for 20 J/cm2 followed by 150 mW/cm2 for a total fluence of 200 to 300 J/cm2 has been used in the treatment of basal cell carcinoma and Bowen's disease [116].
●"In-office painless PDT" – In a prospective split-face study, utilizing 15-minute ALA incubation followed by 60 minutes of continuous blue light exposure resulted in a 52 percent reduction of facial AK lesions with a maximum pain score of only 2 out of 10 [75].
In another prospective, split-face study, topical ALA 20% was applied to the entire face or scalp, and one side was illuminated with blue light immediately (no preincubation with illumination for either 30, 45, or 60 minutes) while the contralateral side received a conventional blue light regimen (one hour ALA incubation with illumination for 16 minutes and 40 seconds) [77]. On the "conventional" side, pain evaluated on a 0 to 10 scale was 4 to 5 as compared with 0.5 to 1 on the "immediate illumination" side. Of note, AK lesion clearance was similar for all three painless regimens, suggesting that a 30-minute, simultaneous ALA/blue light regimen may be an effective, practical, and nearly painless option for facial and scalp AK [77].
Pain relief after treatment
●Topical corticosteroids – Potent topical corticosteroid application just before and after PDT was found to decrease post-treatment erythema without compromising efficacy [117].
●Systemic antihistamines – In a small randomized trial, H1 antihistamines, while not affecting the treatment outcome, were not found to be helpful in relieving post-therapy pain and inflammation [118].
AFTERCARE
●Patients are advised to remain indoors during daylight hours and to avoid bright indoor light for 48 hours after treatment. While indoors, they should stay away from large windows in order to avoid ambient light.
●The area should be gently washed twice daily with a gentle facial cleanser. After cleansing, a bland emollient, such as a petroleum jelly with or without lanolin, can be applied to keep the area moist and free of crust.
●If the skin is irritated or pruritic, a topical corticosteroid ointment can be used once or twice daily for a few days.
●Cool compresses can be applied for comfort as needed.
●By day 4 after treatment, tenderness of the skin should be improved, and twice-daily gentle exfoliation with a soft washcloth and warm water can be initiated. Follow with emollient.
●Shaving of the treated areas should be avoided for several days after treatment.
●If patients must go outdoors, a thick, opaque coat of physical sunscreen (zinc or titanium dioxide), a wide-brimmed hat, and opaque clothing are recommended.
CONTRAINDICATIONS TO PHOTODYNAMIC THERAPY
●Known hypersensitivity to any of the components of the topical photosensitizer.
●Known hypersensitivity to porphyrins.
●Porphyria.
●Photodermatoses.
●Pregnancy or breastfeeding – There are no data available on the use of PDT in this patient population, although systemic absorption of aminolevulinic acid is thought to be negligible following topical administration [54,55,57].
●Children – Although the safety and efficacy of PDT in pediatric patients have not been established, PDT has been used for a variety of skin diseases in children [119].
PATIENT EDUCATION — Patients should be educated prior to the treatment visit about what to expect before, during, and after PDT. An example of handout for patients is shown in the table (table 3).
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Photodynamic therapy for actinic keratosis and nonmelanoma skin cancer".)
SUMMARY AND RECOMMENDATIONS
●Definition and principles – Photodynamic therapy (PDT) is a noninvasive, nonscarring treatment most frequently used for the treatment of nonmelanoma skin cancer and precancerous lesions. PDT involves the application to the skin of a topical prodrug containing aminolevulinate that is converted to protoporphyrin IX (PPIX) within target cancer or precancer cells, followed by illumination with red or blue light to activate the PPIX. The photoactivation of PPIX by wavelengths of light within the visible spectrum, in the presence of oxygen, results in the death of the target cells. (See 'Principles and mechanisms' above and 'Light sources' above and 'Topical photosensitizing medications' above.)
●Indications – PDT is approved by the US Food and Drug Administration (FDA) for the treatment of thin, nonhyperkeratotic actinic keratosis (AK) of the scalp and face. In Europe, Canada, and other countries worldwide, PDT is also approved for the treatment of superficial and thin nodular basal cell carcinoma, when other available therapies are not acceptable, and squamous cell carcinoma in situ. PDT is used off label for the treatment of several skin conditions (table 1). (See 'Clinical indications' above.)
●Standard and modified regimens – Standard PDT regimens are available for the treatment of AK on the face and scalp, but these regimens may need to be modified depending on the patient or the skin disease being treated. (See 'Standard photodynamic therapy regimens for actinic keratoses' above and 'Variations on the standard photodynamic therapy regimen' above.)
●Pain control – Although a short-term side effect, pain associated with PDT can limit its use. Therefore, efforts should be made to enhance patient comfort during and after treatment without decreasing the therapeutic response. (See 'Pain control measures' above.)
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