Photodynamic Therapy
`
`Robert Bissonnette
`
`of oxygen, this leads to generation of reactive oxygen species
`and free radicals. Treatment with plants containing photosen-
`sitizers followed by sunlight exposure was practiced by
` several civilizations since antiquity, but PDT was officially
`discovered at the turn of the twentieth century by Oscar Raab,
`a medical study working in Germany in the laboratory of Von
`Tappeiner.1 The discovery that pre-malignant and malignant
`skin lesions can be treated with topical aminolevulinic acid
`(ALA) application followed by light exposure was made in
`Canada by Kennedy and Pottier in the late 1980s.2
`Aminolevulinic acid (ALA) can enter the heme biosyn-
`thetic pathway which leads to production of porphyrins and
`ultimately of heme, as protoporphyrin IX is transformed into
`heme by the enzyme ferrochelatase. Heme has a negative
`feedback on ALA synthesis. The addition of exogenous ALA
`bypasses this negative feedback leading to accumulation of
`porphyrins which can be activated with visible light (Fig. 1).
`Blue light is the most efficient waveband for porphyrin activa-
`tion but red light is also often used as it penetrates deeper than
`blue light. Following this discovery, researchers experimented
`with several ALA derivatives including methylaminolevuli-
`nate (MAL)3. This ester of ALA also enters the heme biosyn-
`thetic pathway where it is transformed into porphyrins.
`With the approval of ALA and MAL in several countries,
`photodynamic therapy is now a well established procedure in
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`Photodynamic therapy with ALA or MAL is an
`excellent treatment for multiple actinic keratoses
`Large field photodynamic therapy can eradicate
`multiple actinic keratoses with a shorter downtime
`than 5-fluorouracil or imiquimod
`Multiple large field photodynamic therapy sessions
`can delay the appearance of actinic keratoses
`Photodynamic therapy with MAL is approved in
`several countries for the treatment of superficial
`basal cell carcinoma and Bowen’s disease
`Photodynamic therapy with ALA or MAL has
`been successfully used off-label for the treatment
`of acne vulgaris and to improve photoaging.
`Intense pulsed light and pulsed dye lasers can be
`used to activate porphyrins after ALA or MAL
`application
`
`Introduction
`
`•
`
`•
`
`•
`
`Photodynamic therapy was officially discovered
`at the turn of the twentieth century
`The use of photodynamic therapy with ALA to
`treat actinic keratoses and basal cell carcinoma
`was pioneered in Canada by Kennedy and Pottier
`Both ALA and MAL are transformed into porphy-
`rins which can be activated by blue or red light
`
`Photodynamic therapy (PDT) combines the administration of
`a photosensitizer or photosensitizer precursor with its activa-
`tion by light of the appropriate wavelengths. In the presence
`
`R. Bissonnette
`Innovaderm Research Inc., Montreal, Quebec, Canada
`e-mail: rbissonnette@innovaderm.ca
`
`Fig. 1 Accumulation of porphyrins (pink-red) in basal cell carcinomas
`of a patient with Gorlin’s syndrome 3 h after application of ALA.
`Photograph taken under Wood’s lamp
`
`K. Nouri (ed.), Lasers in Dermatology and Medicine,
`DOI: 10.1007/978-0-85729-281-0_18, © Springer-Verlag London Limited 2011
`
`221
`
`
`
`

`

`Photodynamic Therapy
`
`Robert Bissonnette
`
`of oxygen, this leads to generation of reactive oxygen species
`and free radicals. Treatment with plants containing photosen-
`sitizers followed by sunlight exposure was practiced by
` several civilizations since antiquity, but PDT was officially
`discovered at the turn of the twentieth century by Oscar Raab,
`a medical study working in Germany in the laboratory of Von
`Tappeiner.1 The discovery that pre-malignant and malignant
`skin lesions can be treated with topical aminolevulinic acid
`(ALA) application followed by light exposure was made in
`Canada by Kennedy and Pottier in the late 1980s.2
`Aminolevulinic acid (ALA) can enter the heme biosyn-
`thetic pathway which leads to production of porphyrins and
`ultimately of heme, as protoporphyrin IX is transformed into
`heme by the enzyme ferrochelatase. Heme has a negative
`feedback on ALA synthesis. The addition of exogenous ALA
`bypasses this negative feedback leading to accumulation of
`porphyrins which can be activated with visible light (Fig. 1).
`Blue light is the most efficient waveband for porphyrin activa-
`tion but red light is also often used as it penetrates deeper than
`blue light. Following this discovery, researchers experimented
`with several ALA derivatives including methylaminolevuli-
`nate (MAL)3. This ester of ALA also enters the heme biosyn-
`thetic pathway where it is transformed into porphyrins.
`With the approval of ALA and MAL in several countries,
`photodynamic therapy is now a well established procedure in
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`Photodynamic therapy with ALA or MAL is an
`excellent treatment for multiple actinic keratoses
`Large field photodynamic therapy can eradicate
`multiple actinic keratoses with a shorter downtime
`than 5-fluorouracil or imiquimod
`Multiple large field photodynamic therapy sessions
`can delay the appearance of actinic keratoses
`Photodynamic therapy with MAL is approved in
`several countries for the treatment of superficial
`basal cell carcinoma and Bowen’s disease
`Photodynamic therapy with ALA or MAL has
`been successfully used off-label for the treatment
`of acne vulgaris and to improve photoaging.
`Intense pulsed light and pulsed dye lasers can be
`used to activate porphyrins after ALA or MAL
`application
`
`Introduction
`
`•
`
`•
`
`•
`
`Photodynamic therapy was officially discovered
`at the turn of the twentieth century
`The use of photodynamic therapy with ALA to
`treat actinic keratoses and basal cell carcinoma
`was pioneered in Canada by Kennedy and Pottier
`Both ALA and MAL are transformed into porphy-
`rins which can be activated by blue or red light
`
`Photodynamic therapy (PDT) combines the administration of
`a photosensitizer or photosensitizer precursor with its activa-
`tion by light of the appropriate wavelengths. In the presence
`
`R. Bissonnette
`Innovaderm Research Inc., Montreal, Quebec, Canada
`e-mail: rbissonnette@innovaderm.ca
`
`Fig. 1 Accumulation of porphyrins (pink-red) in basal cell carcinomas
`of a patient with Gorlin’s syndrome 3 h after application of ALA.
`Photograph taken under Wood’s lamp
`
`K. Nouri (ed.), Lasers in Dermatology and Medicine,
`DOI: 10.1007/978-0-85729-281-0_18, © Springer-Verlag London Limited 2011
`
`221
`
`
`
`

`

`222
`
`R. Bissonnette
`
`Dermatology. Both drugs are approved to treat actinic kera-
`toses (AK). In addition, MAL is approved in several coun-
`tries, but not in the US, for the treatment of various types of
`non-melanoma skin cancers. Since the approval of MAL and
`ALA, physicians have successfully used these two photosen-
`sitizer precursors for the treatment of several other skin dis-
`eases and have combined them with different lasers, intense
`pulsed light and other non-coherent light sources for porphy-
`rin activation.
`
`Indications and Contraindications
`
`
`
`Indications
`
` Aminolevulinic acid: minimally to moderately
`thick actinic keratoses of the face and scalp
` Methylaminolevulinate: non hypertrophic actinic
`keratoses of the face and scalp
` PDT with MAL is approved in several countries,
`but not in the US, for the treatment of superficial
`basal cell carcinoma and Bowen’s disease
`
`
`
`Contraindications
`
` Porphyria and sensitivity to visible light
`
` Presence of invasive squamous cell carcinoma in
`the treatment field
` Morpheiform basal cell carcinoma
`
` Topical or systemic medications inducing visible
`light sensitivity
` Allergy to MAL
` Warning: MAL contains peanut oil
`
`Indications
`
`Aminolevulinic acid is approved in the US, Canada and
`Brazil for the treatment of minimally to moderately thick
`actinic keratosis of the face and scalp in combination with
`the Blu-U unit (Fig. 2). The original approval was for non-
`hypertrophic actinic keratoses. This has recently been
`changed to minimally to moderately thick AK at the FDA’s
`request. In practice, this wording is similar and refers to the
`fact that PDT is not approved for thick and hypertrophic
`AKs. There are two issues related to treatment of hypertro-
`phic AKs with PDT. The first is inadequate penetration of
`ALA through the hyperkeratotic portion of the lesion and the
`second is the possibility that some of the more hypertrophic
`
`Fig. 2 Blu-U device. This non-coherent light source is approved for the
`treatment of actinic keratoses with ALA
`
`lesions might be micro-invasive SCCs. The current approval
`is based on phase III studies where ALA was applied on vis-
`ible lesions for 14–18 h followed by 10 J/cm2 of blue light
`from a Blu-U unit.4 However, in practice very few physicians
`use ALA-PDT with a 14–18 h incubation. Most will use a
`shorter incubation of 45 min to 2 h. This off label use is sup-
`ported by a small pilot study which showed that incubation
`of 1–3 h in patients with extensive sun exposure leads to AK
`lesion cure rates that are similar to what has been reported
`with longer incubations in phase III studies.5 Complete
`responses on BCC have been reported following ALA-PDT,6
`however the efficacy of ALA-PDT for the treatment of BCC
`has never been studied in multicenter phase III trials and the
`long term recurrence rates have not been well studied.
`MAL is currently FDA-approved for the treatment of non
`hypertrophic actinic keratoses of the face and scalp in immu-
`nocompetent patients when used in conjunction with lesion
`preparation and when other therapies are considered medi-
`cally less appropriate. AK cure rates following either a single
`MAL-PDT session repeated at 3 months if necessary or 2
`MAL-PDT sessions performed 7 days apart have been
`reported to be around 90%.7,8 Studies presented at meetings
`suggest that multiple large surface ALA or MAL PDT ses-
`sions can delay the appearance of new actinic keratoses in
`
`

`

` Photodynamic Therapy
`
`223
`
`organ transplant patients. This suggests that large surface
`PDT may be able to prevent skin cancer.
`Several countries have also granted approval of MAL-
`PDT for the treatment of various non-melanoma skin can-
`cers. The indications vary from one country to another but in
`general most countries approved MAL-PDT for the treat-
`ment of Bowen’s disease and superficial BCC when other
`therapies such as surgery are considered inappropriate.9-11
`The complete response rate of superficial BCC following
`MAL-PDT has been shown to be 97% and the 48-month
`long-term recurrence rate 22%.12,13 The main advantage of
`PDT for the treatment of sBCC and Bowen’s disease is the
`excellent cosmetic outcome as compared to surgery, cryo-
`therapy or electrodessication and curettage.6,9 Some coun-
`tries have also approved MAL-PDT for thin nodular BCC,
`but because the cure rate is lower than with sBCC many
`countries have restricted their approval to sBCC. Recurrences
`for superficial BCCs, nodular BCCs and Bowen’s disease
`usually occur during the first 2–3 years after therapy with no
`increase in recurrence between the third and the fifth year.
`At the time this text was written, MAL was not yet com-
`mercially available in the US because the FDA approved
`MAL only in combination with the Curelight device, an
`
`Fig. 3 Aktilite device. This LED light source is approved in several
`countries for the treatment of AK and/or Bowen’s disease and/or super-
`ficial basal cell carcinoma with MAL
`
`earlier LED light source that is rather cumbersome. In most
`countries MAL is approved with the Aktilite (Fig. 3), a
`smaller and more convenient device. Studies comparing the
`efficacy of Curelight and Aktilite in the treatment of AK are
`currently being completed in the US. These studies should
`lead to FDA approval of MAL-PDT performed with the
`Aktilite device.
`Initial studies conducted with PDT for skin diseases often
`used lasers. However, the current off-label trend with ALA-
`PDT is to use broad area application ALA or MAL in order
`to treat non-visible lesions, improve photoaging and eventu-
`ally prevent the appearance of new lesions. This trend com-
`bined with the cost and limited availability of lasers in the
`400–450 nm and 630–640 nm ranges has limited the use of
`lasers for PDT in Dermatology. When physicians are using
`ALA with a non-approved light source, they tend to favor
`LEDs or intense pulsed light. However, the pulsed dye laser
`at 595 nm has also been used for the treatment of actinic
`keratoses and acne.14
`ALA and MAL have been reported to successfully treat
`various non oncologic skin conditions in small pilot studies
`or in single case reports. These include acne, sebaceous
`hyperplasia, hidradenitis suppurativa and photoaging.14-19
`MAL and ALA are both in phase II for the treatment of acne.
`A number of small controlled studies have shown that MAL
`and ALA can improve acne.14,15,20,21 This is related in part to
`the intense accumulation of porphyrin in sebaceous glands
`following topical application of ALA and MAL (Fig. 4).
`Light exposure could induce partial necrosis of sebaceous
`glands and reduce sebum excretion thus reducing acne
`lesions. Preliminary findings with ALA suggest that this is
`one of the mechanisms of ALA-PDT when used for the treat-
`ment of acne.22 Studies performed with PDT in acne are com-
`plicated by the fact that blue or red light alone can improve
`acne by elimination of propionibacterium acnes as these bac-
`teria naturally accumulate porphyrins.23 The best treatment
`parameters for acne are currently unknown. Most controlled
`studies which have shown good efficacy report a strong post
`PDT phototoxic reaction. Clinical photographs published in
`some of the articles which used MAL under occlusion for 3 h
`show moderate to severe erythema with crusting 1 day post-
`PDT. These publications report severe pain in many patients
`during light exposure.15,21 Such a strong phototoxic reaction is
`probably not needed to see improvement in acne. However, it
`is possible that prolonged remission requires a certain degree
`of phototoxic reaction as necrosis of sebaceous gland tissue
`might be necessary. The current literature suggests that PDT
`for acne is more efficacious for patients with moderate to
`severe inflammatory acne.
`Touma and colleagues have demonstrated that the use of
`ALA-PDT with a 1–3 h incubation followed by blue light
`exposure in patients with multiple actinic keratoses can
`improve photoaging.5 Small wrinkles, pigmentation and
`
`

`

`224
`
`a
`
`b
`
`R. Bissonnette
`
`Fig. 4 ( a) Porphyrin fluorescence in sebaceous glands 3 h after application of MAL. (b) Same section stained with hematoxylin
`
`sallowness were the parameters best improved with ALA-
`PDT. ALA-PDT performed with IPL has also been shown to
`improve photoaging.18,24 Small studies have also shown com-
`plete response in AKs treated with ALA and IPL.24,25 There
`are currently a very wide variety of devices approved and
`used for the treatment of photoaging. Most physicians using
`ALA or MAL-PDT for photoaging either combine PDT with
`other devices and treatments or favor ALA or MAL-PDT for
`patients with actinic keratoses who would also like to have
`improvement in photoaging.
`
`Contraindications
`
`ALA and MAL are contraindicated in patients sensitive to
`visible light corresponding to the spectral output of the light
`source used (400–450 nm for Blu-U and 630–640 nm for
`Aktilite). Patients with porphyria and some patients with
`solar urticaria are also sensitive to visible light. ALA and
`MAL-PDT performed on patients using concomitant photo-
`sensitizing drugs such as phenothiazines, tetracyclines, thi-
`azides and sulphonamide have not been thoroughly studied
`and could theoretically increase the phototoxic reaction seen
`after PDT. Current use of topical or systemic retinoids such
`as tretinoin, adapalene, acitretin or isotretinoin could also
`increase the phototoxic reaction. MAL contains peanut oil. It
`should not contain the protein allergen present in peanuts,
`but many physicians refrain from using MAL-PDT in patients
`allergic to peanuts.
`Histological variants of BCCs that are at high risk of
`recurrence such as morpheiform BCC are a contraindication
`to PDT with MAL. Pigmented basal cell carcinoma is usu-
`ally considered a contraindication to PDT as pigment limits
`light penetration. However several physicians have reported
`complete responses of pigmented BCCs with PDT.
`
`Techniques
`
`Pre-operative management
`
`•
`
`•
`
`•
`
`Informed consent with emphasis on difficulty to
`predict phototoxic response
`Thorough examination of skin areas to be exposed
`to detect malignant lesions
`Consider herpes simplex prophylaxis
`
`Description of the technique
`
`•
`
`•
`•
`•
`
`Skin preparation to enhance penetration (manda-
`tory for MAL)
`Photosensitizer application
`Interval to allow porphyrin build-up
`Light exposure
`
`Post operative management
`
`•
`•
`•
`
`Sun avoidance
`Ferrous oxide containing sunscreen
`Moisturizer
`
`Pre-operative Management
`
`A complete skin examination of the areas to be treated is nec-
`essary. This is of the utmost importance when performing large
`surface PDT. This examination should focus on the identifica-
`tion of malignancies such as basal cell carcinoma, squamous
`cell carcinoma and melanoma. Sub-optimal treatment of these
`malignant lesions could lead to later, deeper recurrences. Any
`suspicious lesion should be biopsied. If PDT is performed to
`treat a malignant lesion such as BCC or Bowen’s disease, a
`
`

`

` Photodynamic Therapy
`
`225
`
`pre-treatment biopsy is recommended. A complete medical
`history including the existence of visible light sensitivity dis-
`eases such as porphyria or solar urticaria should be recorded.
`Patients should be asked about current use of any topical prod-
`uct on the areas to be treated. Products that can alter the stratum
`corneum such as topical retinoids can increase ALA and MAL
`penetration and create a more severe phototoxic reaction fol-
`lowing PDT. The use of systemic treatments that increase vis-
`ible light sensitivity such as St-John’s wort should be avoided.
`Patients should be well informed about the procedure
`including difficulty in predicting the phototoxic reaction gen-
`erated by PDT. If only a few AKs or a single BCC are treated,
`the phototoxic reaction is usually not a problem. However a
`full face treatment can lead to erythema associated with ten-
`derness and sometimes with focal areas of crusting. It is sug-
`gested to obtain a written informed consent which should
`mention this information as well as potential complications
`such as hyperpigmentation, hypopigmentation, scarring
`(mostly when treating basal cell carcinoma), sun and visible
`light sensitivity and prolonged erythema. Patients should be
`advised to bring a hat (when treating the face) or other pieces
`of clothing to cover the area to be treated.
`The risks of triggering light sensitive recurrences of her-
`pes labialis following PDT are currently unknown. For
`patients who experience recurrences following sun exposure,
`antiviral prophylaxis should be discussed.
`Light exposure during PDT sometimes leads to an urti-
`carial reaction immediately after PDT. This is more intense
`when red light is used and when large surfaces are exposed.
`This phenomenon has recently been attributed to histamine
`release by mastocytes and could be prevented by pre-treat-
`ment with antihistamines such as cetirizine.26
`
`Description of the Technique
`
`Treatment of Actinic Keratoses with ALA
`
`A gentle curettage of keratotic AKs should be performed prior
`to ALA application. This is not included in the current product
`monograph but the author finds that this increases the clinical
`response of individual lesions, probably by increasing drug
`
`penetration. Skin preparation is suggested when performing
`short ALA incubations. The face can be washed vigorously
`with acetone or treated with microdermabrasion. Theses tech-
`niques are believed to increase ALA penetration through
`degreasing and/or partial removal of the stratum corneum.
`Microdermabrasion can significantly reduce ALA incu-
`bation time.27 Care should be taken to use the same technique
`with the same pre-treatment method and performed by the
`same person when treating a patient at different sessions as
`differences in skin preparation can have a dramatic impact
`on porphyrin buildup and therefore on the extent of the post-
`PDT phototoxic reaction.
`ALA (Levulan) is available in the form of two glass vials
`inserted in a plastic tube that is covered by cardboard (Fig. 5).
`The two vials should be crushed with fingers and the stick
`shaken for about 3 min to ensure proper mixing of ALA pow-
`der and hydroalcoholic vehicle. ALA should be applied on all
`AKs present in the treatment area. Most physicians will also
`apply ALA on the entire face in order to treat non visible lesions
`and prevent new AKs. Broad area ALA application also has the
`advantage of improving signs of photoaging.5 Care should be
`taken to avoid applying ALA too close to the eyes as inadver-
`tently gets the hydroalcoholic solution will sting if it inadver-
`tently gets into the eyes. Facial zones with more sebaceous
`glands, such as the nose and chin, often display a more impor-
`tant phototoxic reaction than the rest of the face when perform-
`ing PDT. This is probably due to more intense accumulation of
`porphyrins in sebaceous glands. If ALA or MAL is applied on
`these zones during a full face treatment, patients should be told
`to expect a strong phototoxic reaction the day following light
`exposure. A delay of 45 min to 2 h is suggested between ALA
`application and light exposure when ALA-PDT is used on large
`skin surfaces for the treatment of AK. The intensity of the pho-
`totoxic reaction generated by ALA-PDT varies greatly from
`one patient to another and is highly dependent on the type of
`pre-treatment used. For patients with extensive photodamage
`and numerous ill defined AKs, a 45–60 min incubation is usu-
`ally enough and will even sometimes lead to a severe photo-
`toxic reaction post PDT. Some physicians prefer to perform the
`first treatment with a 30–45 min incubation time in these
`patients. The incubation time can be adjusted at subsequent
`treatments based on the phototoxic reaction and the clinical
`response observed.
`
`Fig. 5 ALA (Levulan Kerastick).
`The cardboard has been removed
`to show the 2 glass vials. Areas
`where pressure needs to be
`applied to crush the two glass
`vials are identified in red
`
`

`

`226
`
`R. Bissonnette
`
`After a proper incubation time, patients are placed inside
`the Blue-U device with their eyes protected with appropriate
`eyeshields as the blue light is very intense. As the U-shaped
`unit rotates, treatments can be performed with the patients
`sitting or lying down. The current product monograph rec-
`ommends a light dose of 10 J/cm2 of blue light which corre-
`sponds to an incubation time of 16 min 40 s. This was the
`fluence used in phase III, but a lower fluence is probably
`enough in most patients to completely photobleach porphy-
`rins present in lesions. Many physicians use a shorter incuba-
`tion time, but the efficacy of shorter incubation times has not
`been thoroughly studied in clinical trials.
`Blue light exposure after ALA application generates a
`burning sensation that gradually increases to reach a plateau
`around 3–8 min and is followed by a gradual decrease. This
`decrease in burning sensation intensity corresponds to photo-
`inactivation of porphyrins present in skin lesions. Blue light
`exposure is usually well tolerated by most patients if they
`have been properly warned about the sensation to expect dur-
`ing light exposure. An assistant should be present in the room
`during PDT, especially for the first PDT session, to reassure
`patients and to monitor the burning sensation. The assistant
`can use cool air, spray cool water or even temporarily inter-
`rupt light exposure if pain is too intense.
`
`Treatment of BCC with MAL
`
`A biopsy is suggested before treating a BCC with MAL-PDT.
`The purpose of the biopsy is to confirm the diagnosis and
`exclude histological subtypes, such as morpheiform BCCs,
`for which PDT is contraindicated. Gentle curettage of the
`lesion is mandatory before MAL application as 5 year cure
`rates for MAL-PDT have been established with pre-treatment
`curettage. Figure 6 shows a patient with multiple BCCs before
`and immediately after lesion preparation. MAL is provided in
`
`2g tubes. Once opened the cream must be used within 7 days.
`This allows for treatment of more than one patient with the
`same tube or treatment of the same patient 7 days later with
`the same tube. MAL should be applied on the entire lesion to
`be treated plus a margin of 1 cm and should be occluded (with
`Opsite). Three hours later the occlusion is removed, the cream
`wiped out of the treatment field and the device (Aktilite) posi-
`tioned at 5–8 cm from the skin. There is a risk of under treat-
`ment if the device is positioned beyond 8 cm as the head is flat
`and the irradiance varies according to the distance between
`skin and light source. The area where MAL has been applied
`should be exposed to 37 J/cm2 (Aktilite device) of red light
`which corresponds to approximately 7 min and 30 s.
`
`Post-operative Management
`
`Excess ALA and MAL should be removed by thorough wash-
`ing with tap water to prevent further porphyrin synthesis
`which would make the patient more sensitive to visible light.
`This is especially important when ALA or MAL has been
`applied to large areas such as the entire face. As patients are
`mostly sensitive to the visible part of the electromagnetic
`spectrum, the use of high SPF sunscreens does not provide
`adequate sun protection in the days following PDT. Patients
`can use a sunscreen containing inorganic sunscreening agents
`such as Avene 50 Compact which provides some (but not
`complete) protection.28 Patients should avoid sun exposure or
`exposure to intense visible light such as surgical lighting or a
`high power dentist lamp for 2 days after PDT. Patients should
`avoid driving or walking under the sun on the day PDT is
`performed. They should also be reminded that there is signifi-
`cant visible light exposure even on cloudy days and through
`window glass. There is no visible light sensitivity beyond 2
`days after PDT with ALA or MAL. However, patients should
`
`a
`
`b
`
`Fig. 6 Patient with multiple BCCs (Gorlin’s syndrome) on the back before lesion preparation (a) and immediately after lesion preparation but
`before MAL application (b)
`
`

`

` Photodynamic Therapy
`
`227
`
`use a high SPF sunscreen providing adequate UVA protection
`to prevent hyperpigmentation. The use of Avene thermal
`water, a low mineral content water, after PDT has been shown
`to be superior to a higher mineral content water compara-
`tively for decreasing post treatment pruritus.29
`Crusting and erosions over AK and BCC is expected and
`desirable when treating malignant or pre-malignant lesions
`with PDT. Simple occlusion combined with the use of petro-
`latum jelly or an antibiotic ointment is usually all that is
`required to promote healing and to decrease pain. Regular
`use of a bland moisturizer is recommended. Patients should
`avoid any topical products containing urea, retinoic acid or
`other alpha hydroxyl acids, alcohol or propylene glycol in
`the days and weeks following PDT. Patients should be
`advised to call if the reaction increases beyond 2 days as this
`may be suggestive of bacterial infection or reactivation of
`extensive herpes simplex.
`
`Adverse Events
`
`Expected
`
`•
`•
`•
`
`Erythema
`Burning sensation during light exposure
`Crusting on AKs and BCCs
`
`Possible
`
`•
`•
`•
`•
`
`•
`•
`•
`•
`
`Pain after light exposure
`Hyperpigmentation
`Hypopigmentation
`Scarring by loss of substance (e.g., nodular basal
`cell carcinoma)
`Urticarial reaction on exposed area
`Prolonged erythema
`Cellulitis, impetigo
`Reactivation of herpes simplex
`
`Side Effects/Complications
`
`Most patients will report a burning sensation, pain or pruritus
`during light exposure. This is usually well tolerated. When
`large surfaces are treated with MAL or ALA, the use of water
`spray, fan or cold air (such as from a Zimmer device) can
`alleviate this sensation. Temporary interruption of light
`exposure is another alternative as the burning sensation sub-
`sides rapidly when the light device is turned off.
`All patients should expect a phototoxic reaction after
`PDT. The absence of a phototoxic reaction on pre-malignant
`
`or malignant lesions following PDT is usually a sign that the
`treatment will not be efficacious. The phototoxic reaction
`manifests itself primarily by erythema on exposed sites that
`can vary from mild to severe. This is usually associated with
`crusting on areas were AKs were present and sometimes
`associated with vesicles, pustules and/or erosions. Erythema
`and edema are often more severe when the lesion to be treated
`is located on the nose. This is probably related to the abun-
`dance of sebaceous glands on the nose. Tenderness is usually
`present for a few days after PDT. Whole face treatments are
`often associated with pain and tenderness that are exacer-
`bated with pressure (contact with pillow when sleeping for
`example) and followed by desquamation.
`Bacterial infections such as impetigo and/or cellulitis or
`reactivation of herpes simplex are possible but very rarely
`seen with ALA and MAL-PDT. PDT can induce hyperpig-
`mentation on treated areas. This is rarely seen in patients
`with phototype I or II. Hypopigmentation is possible but
`rare. Scarring by loss of substance can be seen after treat-
`ment of lesions that invade the dermis such as nodular basal
`cell carcinoma.
`A few cases of prolonged erythema have been reported fol-
`lowing PDT on the face.30 This phenomenon can sometimes
`last many months. In the author’s experience, this is more fre-
`quent in patients with rosacea and usually fades over time.
`Allergy to MAL has been reported and documented by
`patch testing.31 Clinicians should think about this possibility
`in patients who have undergone several MAL-PDT treat-
`ments and present with a dermatitis type of reaction that was
`not present at previous treatments.
`
`Prevention and Treatment
`of Side Effects/Complications
`
`As discussed in the post operative management section,
`application of petrolatum jelly, a bland moisturizer or an
`antibiotic ointment will make the phototoxic reaction more
`tolerable.
`Removal of MAL and ALA after PDT is important in order
`to reduce the continuous synthesis of porphyrin which increases
`post-treatment sensitivity to visible light. Patients should thor-
`oughly wash their face with soap and water after light expo-
`sure. In a small pilot study where MAL was applied for 3 h
`under occlusion, porphyrin fluorescence was maximum at 1 h
`after cream removal but there was enough porphyrin present in
`the skin at 24 h after MAL application to induce a phototoxic
`reaction following light exposure in 6 out of 16 subjects.32
`Patients must be warned to avoid sun exposure for 2 days
`after PDT. The use of a sunscreen containing the physical
`sunscreening agent iron oxide such as Avene Compact 50 is
`recommended during the first 2 days. Sun protection with a
`
`

`

`228
`
`R. Bissonnette
`
`high SPF sunscreen with good UVA protection is also impor-
`tant during the weeks following PDT in order to prevent
`hyperpigmentation.
`
`Future Directions
`
`•
`•
`•
`•
`•
`
`Treatment of acne
`Treatment of sebaceous hyperplasia
`Treatment of hidradenitis suppurativa
`Prevention of skin cancer with larger surface PDT
`Development of new photosensitizers
`
`PDT with ALA and/or MAL is now a well established treat-
`ment modality for actinic keratoses, basal cell carcinoma
`and/or Bowen’s disease. Some studies have suggested that
`large surface ALA or MAL PDT could prevent AK and
`maybe even SCC. Further prevention studies are needed in
`patients with multiple AKs, SCCs and BCCs. There is evi-
`dence that PDT performed with these photosensitizers has
`good efficacy in the treatment of acne vulgaris and both are
`currently in phase II for this indication. Future studies should
`determine the best treatment parameters to obtain improve-
`ment in acne vulgaris while limiting the phototoxic reaction.
`Other areas where MAL and/or ALA PDT has shown prom-
`ising efficacy include sebaceous hyperplasia and hidradenitis
`suppurativa.
`New photosensitizers are also currently being studied in
`phase I/II for various skin diseases including acne and hair
`removal. This should lead to more dermatological applica-
`tions for PDT in the coming years.
`
`Conclusion
`
`Photodynamic therapy with ALA and MAL is currently
`widely used for the treatment of actinic keratoses, superficial
`basa