>> Clinical Guidelines

Guidelines for topical photodynamic therapy: report of a workshop of the British Photodermatology Group

C.A.MORTON, S.B.BROWN,* S.COLLINS,† S.IBBOTSON,‡ H.JENKINSON,§ H.KURWA,¶ K.LANGMACK,** K.MCKENNA,†† H.MOSELEY,‡ A.D.PEARSE,‡‡ M.STRINGER,§§ D.K.TAYLOR,¶¶ G.WONG*** AND L.E.RHODES†††
Department of Dermatology, Falkirk Royal Infirmary, Falkirk FK1 5QE, U.K.
*Department of Biochemistry and Molecular Biology, and §§Centre for Photobiology and
Photodynamic Therapy, University of Leeds, Leeds, U.K.
†Department of Dermatology, Beaumont Hospital, Dublin, Ireland
‡Photobiology Unit, Department of Dermatology, Ninewells Hospital, Dundee DD1 9SY, U.K.
§Department of Dermatology, White Abbey Hospital, Newtonabbey BT39 9RH, U.K.
¶Department of Dermatology, Churchill Hospital, Oxford OX3 7LJ, U.K.
**Department of Radiotherapy, St George's Hospital, Lincoln, U.K.
††Department of Dermatology, Belfast City Hospital, Belfast BT9 7AB, U.K.
‡‡Department of Dermatology, University of Wales College of Medicine and University Hospital of Wales, Cardiff CF14 4XN, U.K.
¶¶Department of Medical Physics, Gloucestershire Royal Hospital, Gloucester GL1 3NN, U.K.
***Department of Dermatology, Royal Liverpool Hospital, Liverpool L7 8XP, U.K.
†††Photobiology Unit, Dermatology Centre, University of Manchester, Hope Hospital, Salford M6 9HD, U.K.

Accepted for publication 6 December 2001

Correspondence: Dr C.A.Morton
Email: colin.morton@fvah.scot.nhs.uk

Summary

Topical photodynamic therapy (PDT) is effective in the treatment of certain non-melanoma skin cancers and is under evaluation in other dermatoses. Its development has been enhanced by a low rate of adverse events and good cosmesis. 5-Aminolaevulinic acid (ALA) is the main agent used, converted within cells into the photosensitizer protoporphyrin IX, with surface illumination then triggering the photodynamic reaction. Despite the relative simplicity of the technique, accurate dosimetry in PDT is complicated by multiple variables in drug formulation, delivery and duration of application, in addition to light-specific parameters. Several non-coherent and coherent light sources are effective in PDT. Optimal disease-specific irradiance, wavelength and total dose characteristics have yet to be established, and are compounded by difficulties comparing light sources. The carcinogenic risk of ALA-PDT appears to be low. Current evidence indicates topical PDT to be effective in actinic keratoses on the face and scalp, Bowen's disease and superficial basal cell carcinomas (BCCs). PDT may prove advantageous where size, site or number of lesions limits the efficacy and /or acceptability of conventional therapies. Topical ALA-PDT alone is a relatively poor option for both nodular BCCs and squamous cell carcinomas. Experience of the modality in other skin diseases remains limited; areas where there is potential benefit include viral warts, acne, psoriasis and cutaneous T-cell lymphoma. A recent British Photodermatology Group workshop considered published evidence on topical PDT in order to establish guidelines to promote the efficacy and safety of this increasingly practiced treatment modality.

Key words: 5-aminolaevulinic acid, guidelines, non-melanoma skin cancer, protoporphyrin IX, topical photodynamic therapy

Topical photodynamic therapy (PDT) with 5-aminolaev-ulinic acid (ALA) is a potentially advantageous treatment modality (Table 1). First described by Kennedy et al. in 1990¹, the proliferation of case reports and case series that followed supported the efficacy of the therapy, particularly in non-melanoma skin cancer (NMSC). However, beyond brief consideration in guidelines on treatment of Bowen's disease and basal cell carcinoma (BCC), there remains no consensus on optimal methodology or therapeutic indications^2,3. In the U.K., 35 centres currently perform topical ALA-PDT (personal communication, Crawford Pharmaceuticals, U.K.) despite its status as an unlicensed therapy, with topical ALA available only on a named-patient basis. In November 1999, the U.S. Food and Drug Administration approved ALA-PDT (using Levulan and the Blu-U lamp) for the treatment of actinic keratoses⁴. In June 2001, the methyl ester of ALA (Metvix ) was approved in Sweden for topical PDT of non-hyperkeratotic actinic keratoses of the face /scalp and for BCCs unsuitable for conventional therapy (personal communication, Photo-cure ASA, Norway). Approvals for the rest of Europe are expected in the near future.

The increasing clinical use of topical ALA-PDT indicates a pressing need for a review of available evidence on how and when dermatologists should consider using this modality. The guidelines presented result from a British Photodermatology Group workshop held in November 2000 and are based, where available, on the data from randomized trials, and otherwise on the consensus of best practice (Appendix 1).

Table 1. Advantages of topical 5-aminolaevulinic acid-photodynamic therapy

Relatively selective treatment
Minimal or no scarring
Non-invasive
Multiple lesions may be treated simultaneously
Safe
Out-patient procedure
Repeated treatments possible

Drugs and method of action

The photodynamic reaction requires activation of photosensitiser in neoplastic/dysplastic tissue, by visible light and in the presence of oxygen, to produce reactive oxygen species, especially singlet oxygen, which promote tumour destruction⁵. Initially, haematoporphyrin derivatives and porfimer sodium were the photosensitisers used in cutaneous malignancy, but systemic administration and the consequent prolonged generalised photosensitivity, which can last 6-10 weeks, limited their use⁶. Systemic photosensitisers with a shorter duration of action are currently under exploration in dermatology.

Topically active agents are preferable for PDT in dermatology, and most experience to date has been with ALA. This is a precursor in the haem biosynthesis pathway, in which the endogenous photosensitiser protoporphyrin IX (PpIX) is formed, which binds with iron to form haem. Exogenous administration of ALA can increase the intracellular concentration of PpIX to therapeutically useful concentrations by bypassing a cell's feedback control, although it is metabolized within 48h, conveniently avoiding prolonged phototoxicity. Preferential accumulation of PpIX appears to result from increased penetration of ALA through the abnormal epidermis overlying tumours, and to preferential intracellular accumulation of PpIX in proliferating, relatively iron-deficient, tumour cells⁷.

Meso-tetraphenylporphinesulphonate tetrasodium (mTPPS) and mesotetra (hydroxyphenyl)chlorin (mTHPC) are other photosensitisers that have been applied topically, with disruption of lysosomes being central to their action^8,9.  Only single open studies of their use are described. mTPPS cleared 94% of 292 superficial BCCs with a single treatment and a 10% recurrence rate, but its development has been limited by prolonged photosensitivity and the potential for neurotoxicity⁸. mTHPC has a longer absorption maximum at 652 nm than ALA and mTPPS (both 630-635 nm) and might improve efficacy by utilizing light with deeper tissue penetration. In the sole study of its topical use, a histological clearance of only nine of 28 patches of Bowen's disease and two of seven BCCs was achieved, and formulation was considered to be a problem⁹. These agents will not be considered further in view of the limited data and current lack of evidence of any superiority over ALA-PDT.

Beyond direct tumour cell cytotoxicity, photodynamic injury to tumour vasculature probably contributes little in PDT using topically administered photosensitisers, with no direct vascular damage demonstrated by laser Doppler perfusion imaging in one study of NMSC^10.

Drug protocols and delivery

For optimal effect, a photosensitiser should demonstrate maximum absorption at the wavelength of light used, penetrate the deeper levels and be evenly distributed throughout the lesion, and demonstrate a high lesion /normal tissue concentration ratio. The absorption peaks of PpIX are all within the visible spectrum and permit illumination by laser and non-coherent sources¹¹. Fluorescence emitted by ALA-induced PpIX is an effective method of determining the distribution of the photosensitiser and can be assessed by in vivo spectroscopy and fluorescence microscopy. Szeimies et al¹². used fluorescence microscopy to show homogeneous fluorescence of nodular and superficial, but not morphoeic BCCs, also including tumour lobules in deep dermis, 12h after 10% ALA application, with only skin appendages demonstrating fluorescence in specimens analysed after a 4h application. Martin et al¹³. also used fluorescence microscopy to observe full-thickness fluorescence in six of seven superficial BCCs and four of nine nodular BCCs after 20% ALA application at intervals of 3-18h. Partial-thickness fluorescence in the five remaining (and overall thicker) nodular BCCs was noted typically in the superficial part of the tumours. Roberts and Cairnduff¹⁴ reported that PpIX distribution in BCC was most intense in those regions of tumour immediately adjacent to the dermis following application of 20% ALA for 4h to Bowen's disease and superficial BCC.  Svanberg et al⁷. reported a 15 : 1 tumour/normal tissue ratio of PpIX-induced fluorescence in BCC and Bowen's disease 6h following the topical application of ALA, indicating the potential for a high degree of tumour specificity. However, much of the intense surface fluorescence was due to tumour-reactive epithelium, rather than actual tumour cells, and a ratio of 2 : 1 is more representative for tumour /dermis.

ALA is hydrophilic, but to facilitate penetration, most studies report the use of a 20% concentration in an oil-in-water emulsion. A single study using a nanocolloid lotion of ALA in treating BCC was effective, but no comparative data on different formulations exist¹⁵. ALA delivery through human skin can be assisted by iontophoresis, which provides an accurate means of drug dosimetry, although the usefulness of this method in clinical practice remains to be demonstrated¹⁶.  Enhancement of ALA-PDT has been studied using the penetration enhancer dimethylsulphoxide (DMSO) and the iron chelators desferrioxamine and ethylenediamine tetraacetic acid disodium (EDTA). Only open case series of efficacy are reported in NMSC indications^17-20, although, in a sequential three-stage study, Warloe et al²¹. treated BCCs using ALA alone, ALA with 2-20% DMSO + 2-4% EDTA as cofactors, or ALA and pretreatment with 50-99% DMSO. Outcomes were similar for superficial lesions, but an increase in efficacy using enhancers was observed for nodular BCC, suggesting a need for randomised comparison data.  Enhanced response in ALA-PDT may also be achieved by prior debulking curettage in nodular BCC, although again no comparative data have been published²². Esterified derivatives of ALA that increase its lipophilicity could potentially enhance efficacy. In non-lesional skin, equimolar concentrations of the hexyl and pentyl ester, but not butyl ester, promote higher PpIX levels and greater PpIX-induced phototoxicity than ALA^23,24.  PDT with ALA methylester (Metvix ) has achieved high response rates in actinic keratoses and BCC, although no comparison data with ALA are published^25,26.  An open study of 94 patients with high-risk..BCC (mid-face, large or recurrent), for which conventional therapy was unsuitable, showed a 74% histological clearance rate and 75% good or excellent cosmetic outcome after fractionated Metvix-PDT²⁷. The results of a randomized study of excision surgery vs. topical Metvix PDT for primary BCC await publication.

Reported application intervals for ALA vary from 3 to 48h, with 4-6h extensively studied¹⁴. The optimal preillumination interval is probably disease dependent; only one non-randomized comparison study is published, suggesting that a 6h application may be superior to a 4h one for superficial BCC up to 2 mm thick²⁸.

Light sources and dosimetry

Several light sources have been used in clinical PDT studies for cutaneous applications, including lasers, xenon arc/discharge lamps, incandescent filament lamps and solid-state light-emitting diodes (LEDs). Limited randomised comparison data exist, although one study demonstrated an equivalent response of BCC to ALA-PDT with light delivered from either a copper vapour pumped dye laser or a broadband incandescent halogen source²⁹. Most sources seek to utilize the 'red' 630 nm absorption peak of PpIX in order to maximize tissue penetration, although the emission of one fluorescent lamp is centred on the maximum, but least penetrating 'blue' 410 nm peak, and several broad-band lamps can activate smaller peaks at 505, 540 and 580 nm (Table 2)¹¹. The contribution of emission wavelengths beyond 630 nm that may activate PpIX photoproducts (640-670 nm) is not known, but this probably has little therapeutic effect³⁰. Comparison of light sources requires consideration of their relative efficiency, as estimated by mapping their spectral output to PpIX absorption, as well as total power, size of illumination field, ease and cost of use, and flexibility to adapt to the use of other photosensitisers.

Choice of light source may also be influenced by intended application(s). Red light may penetrate up to 6 mm, compared with 1-2 mm for light at 400-500 nm, depending on the tissue; however, in skin where light scatter is high, the therapeutically effective depth of ALA-PDT is likely to be considerably less, i.e. 1-3 mm at 630 nm⁵. Blue light and green light are reported to be effective in actinic keratoses⁴, with green light as effective as red light in one half-side non-randomized comparison of six patients³¹. In a randomised comparison of green with red light in Bowen's disease (61 lesions), however, green light was significantly inferior, suggesting that deeper light penetration to include skin appendages is required in Bowen's disease³².

Clinical protocols for topical ALA-PDT can presently be defined only in terms of explicit parameters, including the administered ALA dose (and vehicle), the drug-illumination interval, and the wavelength /band, fluence rate or irradiance (mW cm ^-2) and fluence or dose (J cm ^-2) of externally delivered light. Total effective fluence, taking into account incident spectral irradiance, optical transmission through tissue and absorption by photosensitiser, has been proposed as a concept for more accurate dosimetry taking account of the variety of light sources available³³. In practice, light dosage is usually estimated from the energy fluence, due to the difficulty in determining other parameters. Comparison of dosimetry in studies using different broadband sources is thus prevented, as a significant proportion of incident light may be of relatively ineffective wavelengths.

Fluence rates greater than 50 mW cm ^-2 may begin to affect oxygen availability in ALA-PDT, and rates over 150 mW cm ^-2 may induce hyperthermic injury^34,35.  A recently described mathematical model of photodynamic damage predicts that low fluence rates can be as effective as high-rate illuminations if performed over the same time³⁶. The spectral output of certain incandescent light sources, e.g. xenon arc, metal halide and tungsten /halogen, includes infrared, which is usually removed as it will contribute to tissue heating, possibly increasing the risk of scarring. Fractionation (discontinuous illumination) may improve tumour responsiveness by permitting tissue reoxygenation during dark periods, although its importance in topical ALA-PDT of cutaneous malignancy has not been studied. Optimal light dose is likely also to be disease specific, with high tumour-killing doses used in NMSC (54-540 J cm ^-2); this is in comparison with almost complete photo-oxidation (photobleaching) of psoriatic plaques observed after 16 J cm ^-2 in studies using modified slide projectors^1,37. It is recommended that all relevant information about the source, model type, bandwidth, intensity and uniformity should be given in clinical reports.

Published studies indicate that several light sources are effective in promoting the NMSC applications of ALA-PDT (strength of recommendation A, quality of evidence IIiii). At present, no single light source is ideal for every possible indication for topical PDT. Choice should be based on the proposed clinical indications (including number and size of lesions), priorities for a portable compact source with a smaller field size vs. a bulky fixed large field-size source, flexibility, treatment times and cost.

Indications for topical photodynamic therapy

Actinic keratoses
In six open studies of ALA-PDT of 323 actinic keratoses situated on the face and scalp in caucasian populations, clearance rates ranged from 71 to 100% after a single treatment^1,38-42 Itoh et al⁴³. recently reported the efficacy of ALA-PDT for actinic keratoses in Oriental patients with a clearance rate of 82% for facial lesions, although three to six treatments were required. Jeffes et al⁴⁰. noted no difference in response between 10% and 30% preparations of ALA, with application times typically ranging from 3 to 6h. Several lamps have been used, but even in the two studies that employed two light sources, no randomisation was performed and dosimetry differed, preventing comparison^41,43. Green light may be as effective as red for actinic keratoses³¹, with less pain reported. A blue light source (Blu-U , delivering 10 J cm ^-2 at 10 mW cm ^-2) is licensed for the treatment of non-hyperkeratotic actinic keratoses of the face and scalp, with an ALA formulation (Levulan Kerastick ) applied 14-18h prior to illumination. A complete clearance rate for patients of 66% after one treatment is reported, rising to 72% by 12 weeks following a second treatment, where required⁴.

Four studies report the inferiority of response of acral actinic keratoses in comparison with facial lesions, with weighted clearance rates of 44% (105 of 240) compared with 91% (286 of 315)^39,40,43,44. Kurwa et al⁴⁵. Compared ALA-PDT with topical 5-fluorouracil in a randomised comparison study of 17 patients with extensive disease affecting both hands. The reduction in lesional area on the hand randomised to a single treatment with ALA-PDT (73%) was almost identical to that following 5-fluorouracil application (71%). Histopathological confirmation of clearance is rarely undertaken, although Calzavara-Pinton⁴⁶ observed persisting disease in three of 17 apparently clear sites histologically sampled in a study of 50 lesions. He followed up patients for 24-36 months, recording a 10% recurrence rate. Szeimies et al⁴⁷. performed a randomised multicentre comparison of 699 actinic keratoses using methyl 5-aminolaevulinate-based PDT in comparison with cryotherapy. Of the actinic keratoses studied, 93% were thin or of moderate thickness and 92% were situated on the face or scalp. Overall response rates, at 3 months, to a single treatment session were similar between the groups (69% for PDT, 75% for cryotherapy), but cosmetic outcome was superior in the PDT group. ALA-PDT, and possibly also methyl 5-aminolaevuli-nate-PDT, are effective in clearing non-hyperkeratotic actinic keratoses on the face and scalp, with response rates comparable with topical 5-fluorouracil and cryotherapy, although with a cosmetic response superior to that with cryotherapy (strength of recommendation A, quality of evidence I).

Bowen's disease
Topical PDT using 20% ALA has been extensively assessed in Bowen's disease [squamous cell carcinoma (SCC) in situ] with 13 open (pilot and case series)^{1,7,20,46,48-56} and three randomised comparison studies^32,57,58. A single ALA-PDT treatment cleared 86% (weighted complete clearance rate, six studies, 71 of 83), rising to 93% (nine studies, 239 of 257) of lesions if one or two repeat treatments were permitted in the protocol. The recurrence rate ranged from 0 to 40%, average 12%, during follow-up periods of 3-36 months. Most studies were small, with seven of 16 treating only three to 10 lesions. Protocols differed, with laser, tungsten, xenon and LED sources used. An application time of ALA of 3-6h was widely practiced, with extension to 20h in one study in which only five of 10 patches of Bowen's disease were cleared²⁰. ALA-PDT is also effective in the closely related entity erythroplasia of Queyrat, with a case series reporting clearance in two patients and partial response in another two who had more extensive disease⁵⁹. The subsequent development of an SCC at the treatment site in a separate case report (see below) emphasizes the need for close follow-up⁶⁰.

The optimum wavelengths for treating Bowen's disease are not defined, although the preference for more penetrating red light is supported by a randomised comparison study of 59 lesions, which demonstrated a significantly higher clearance rate with red light (630 ± 15 nm) than green (540 ± 15 nm)³².

Two randomized studies compared topical ALA-PDT with conventional therapy^57,58. ALA-PDT was at least as effective as cryotherapy (one or two PDT visits, one to three cryotherapy visits) in clearing 20 small patches of Bowen's disease. PDT demonstrated a significantly higher rate of clearance after a single treatment (75% vs. 50%)⁵⁷. Adverse events were only observed in the cryotherapy group: ulceration (five of 20), infection (two of 20) and scar formation (four of 20). A randomised trial comparing ALA-PDT with topical 5-fluorouracil (one or two treatment cycles in each group) showed that PDT was also at least as effective at 8 months follow-up, with fewer adverse reactions⁵⁸. No comparison data with radiotherapy, surgery or curettage exist.

Topical ALA-PDT may be particularly useful for large and multiple patches of Bowen's disease. The clearance, by ALA-PDT, of three large patches of Bowen's disease, 40-80 mm in diameter, has been supported by a recent study of 40 large (20-55 mm) lesions^52,56. An initial clearance rate of 88% after one to three treatments fell to 78% by 12 months. In the same study, 10 patients with 45 patches of Bowen's disease saw an overall clearance rate with PDT of 89% after 12 months. The absence of serious adverse events and observed good cosmesis were again noted.

In summary, ALA-PDT is effective in Bowen's disease, achieving good cosmesis, and is at least as effective as cryotherapy or 5-fluorouracil, but with fewer adverse events. Topical PDT may offer advantages over existing modalities for large or multiple lesions, those in poor healing sites such as the lower leg, and for penile, digital and facial lesions where existing treatments have recognised limitations (strength of recommendation A, quality of evidence I).

Basal cell carcinoma
The weighted average complete clearance rates, after follow-up periods of 3-36 months, were 87% and 53%, respectively, in 12 studies treating 826 superficial and 208 nodular BCCs reviewed by Peng et al³⁴ For tumours up to 1 mm thick, initial clearances of 81% (26 of 32), 95% (59 of 62) and 100% (36 of 36) were reported after one or two treatments (4-6h ALA application), although with recurrence rates by 12-24 months of 16%, 18% and 6%, respectively^28,36,55.  Limited data on the depth of response are available for thicker superficial BCCs, although six of six up to 2 mm thick, treated at 6h, cleared without recurrence over 6-16 months²⁸. Morphoeic and pigmented lesions respond poorly to PDT³⁴.

The inferior response of nodular BCCs, with their lack of homogeneous uptake of photosensitiser^13,14, led Warloe et al²¹ to perform a non-randomised comparison of ALA-PDT with penetration enhancers. DMSO + EDTA increased clinical clearance rates from 67% to 90% for nodular BCCs <2 mm, and from 34% to 50% for thicker lesions. Prior debulking curettage by Thissen et al.,²² 3 weeks pre-PDT, achieved a 92% clinical and histological response rate in 24 nodular BCCs when all treated skin areas were excised at 3 months. Soler et al⁶¹. similarly cleared 92% of 119 nodular lesions by penetration enhancement and curettage, with 95% of lesions remaining clinically clear after 17 months (range 12-36). Prior surface shaving probably also enhanced response rate to 90% in 10 nodular BCCs treated by PDT with ALA methylester applied for 3h²⁶.

Only one randomised comparison study has been published of ALA-PDT with cryotherapy for both superficial and nodular BCCs, with no significant difference in efficacy, although with fewer adverse events, shorter healing times and superior cosmesis following PDT⁶². Caution in interpreting short-term follow-up studies is advised following the observation in this study of a recurrence rate following PDT at 12 months, by clinical examination of 5%, but of 25% when verified by histopathology at the same visit. Presently, there are no 5-year follow-up data, and, therefore, no direct comparison of ALA-PDT can be made with conventional therapies⁶³.

A complete clearance rate of 96% at 12 months for superficial BCC has suggested the importance of technique, with a double treatment 7 days apart yielding results superior to the same group's 50% complete clinical response rate after a single treatment^48,64. Patients with large and multiple superficial BCCs may particularly benefit from topical PDT^53,55,56, although the response of patients with naevoid basal cell epithelioma syndrome has been disappointing with only 11 of 18 (61%) superficial tumours and 3 of 26 (12%) nodular lesions clearing in one study²¹.

Guidelines published by the British Association of Dermatologists in 1999 on the treatment of BCC list excision or cryotherapy as the treatments of choice for most presentations³. PDT was considered an investigational tool that probably should not be used in BCC. Although licensing for BCC treatment is awaited, current evidence indicates topical ALA-PDT to be an effective therapy for superficial (<2 mm thick) BCC, at least as effective as cryotherapy, but with superior healing and cosmesis, and with particular advantages in large and multiple lesions (strength of recommendation A, quality of evidence I). Topical ALA-PDT is, less effective for nodular BCC, and although adjunctive therapy with prior curettage or with penetration enhancers, or fractionated treatment may improve results, there is no published randomised evidence of their benefit (strength of recommendation C, quality of evidence IIiii).

Squamous cell carcinoma
In three open studies^46,53,63 of topical PDT in the treatment of SCC, there was an initial response rate of 54-100% (69% weighted average; 52 of 75) for superficial lesions, but recurrence rates of up to 69% (average 24%; 12 of 49) after 3-47 months. Only four of 10 nodular tumours remained clear after 12-36 months^46,53. Fritsch et al⁵³. achieved a 79% clearance rate after 12-24 months in 28 superficial lesions. Calzavara-Pinton⁴⁶ clinically cleared 92% (11 of 12) of superficial SCCs, 6-8h after ALA application, with a pathologically confirmed clearance rate at 24-36 months of 83%. Fink-Puches et al⁶³. treated 35 superficial SCCs with ALA followed by exposure to either ultraviolet A or different wavelengths of polychromatic visible light. A complete response with all wavelengths of light was obtained for 54%, but with a 69% recurrence rate after a mean follow-up of 8 months (range 3-47).  Despite a few encouraging results, in view of its metastatic potential and high recurrence rates, caution is currently advised in using topical ALA-PDT to treat SCC (strength of recommendation D, quality of evidence IIiii).
 

Applications for topical 5-aminolaevulinic acid-photodynamic therapy other than in
non-melanoma skin cancer

Topical PDT has been applied in small case series, with encouraging results in actinic cheilitis⁶⁵, condylomata acuminata⁶⁶, keratoacanthoma⁴⁶, lichen sclerosus⁶⁷ and scleroderma⁶⁸. There are isolated reports of efficacy in the treatment of epidermodysplasia verruciformis⁶⁹, hirsutism⁷⁰, lichen planus⁷¹, naevus sebaceus⁷² and others. Disappointing results have been seen with topical PDT for breast cancer metastases^1,48 and malignant melanoma³⁸.  The use of topical PDT in the treatment of vulval intraepithelial neoplasia (VIN) indicates benefit with multiple treatments⁷³, with histological grade of VIN as a determinant of response⁷⁴, and lack of response with single-treatment PDT for VIN type III⁷⁵. The use of topical PDT as monotherapy for extramammary Paget's disease is controversial as reports are mainly in combination with other therapies⁷⁶; however, clearance of recurrent disease with intralesional ALA and multiple treatments has been shown in one subject77. In view of limited evidence, no recommendations are proposed concerning the above indications, except for breast metastases and VIN, where there is currently poor evidence to support its use (strength of recommendation C, quality of evidence IIiii). A recent randomised controlled trial has demonstrated a lack of effect of ALA-PDT in alopecia areata⁷⁸ (strength of recommendation D, quality of evidence I).

Most studies on non-NMSC applications for ALA-PDT concern warts, acne, psoriasis and cutaneous
T-cell lymphoma (CTCL) (Table 3).

Warts (strength of recommendation B, quality of evidence I)
Despite a report of lack of efficacy of single-treatment ALA-PDT in the treatment of viral warts⁷⁹, subsequent case series and comparison trials reported by Stender et al^80-83. achieved clearance rates of 56-100%, and demonstrated superior efficacy of repetitive ALA-PDT compared with cryotherapy or placebo-PDT. In a comparative study, white light PDT was more effective than red or blue light PDT or cryotherapy in patients with refractory warts and verrucas⁸¹.  A subsequent, randomised study demonstrated superior efficacy of ALA-PDT compared with placebo-PDT, with endpoints of significant reduction in the wart area and increased rate of clearance with the active treatment group⁸³.  However, a significant side-effect of treatment was pain, which may limit use, particularly in children. Successful PDT to recalcitrant warts would appear also to require lesion paring pretreatment, with additional paring with or without topical keratolytic treatment during the study period.

Acne (strength of recommendation B, quality of evidence I)
A recent study in patients with mild to moderate acne showed superior efficacy of a combination of red and blue light phototherapy in improvement of both comedonal and inflammatory acne⁸⁴. Although treatment was without the use of an exogenous photosensitiser, the mechanism of action is likely to include endogenous PDT of porphyrins in Propionibacterium acnes. The use of ALA-PDT has been examined in an open placebo-controlled study in 22 subjects with moderate truncal acne, showing reduction in sebum production, P. acnes fluorescence, sebaceous gland size and clinical acne for up to 20 weeks after multiple treatments⁸⁵. Furthermore, Itoh et al. reported prolonged benefit for several months after low-dose, single-treatment ALA-PDT^86,87.  These findings provide encouraging evidence that ALA-PDT may be a useful adjunct in certain types of acne, but discomfort during treatment, crust formation, erythema and pigmentation for up to 4 weeks after treatment may limit patient acceptance of this therapy.

Psoriasis (strength of recommendation C, quality of evidence IIiii)
Photobleaching during topical PDT for psoriasis is established, and the same authors demonstrated efficacy of three times weekly topical PDT comparable with dithranol^88,89. Subsequent studies have shown marked variation in PpIX fluorescence in psoriatic plaques after ALA application and in treatment response and discomfort experienced^37,90,91. Multiple treatments improved clinical outcome, although this remained unpredictable and pain was a limiting factor⁹².  At present, the optimal regimen for topical PDT for psoriasis has not been established and the limitations of variation in photosensitiser accumulation, therapeutic response and pain preclude its use in clinical practice.

Cutaneous T-cell lymphoma (strength of recommendation C, quality of evidence IIiii)
Selective uptake of photosensitisers into lymphocytes after topical PDT, with inhibition of T cells and photobleaching, has been demonstrated in topical PDT of CTCL using a mixture of porphyrins, including PpIX⁹³. Repetitive treatments with topical ALA-PDT resulted in clinical and histological remission in two patients with plaque-stage CTCL but, in another case, clinical but not histological clearance was observed after one treatment, emphasizing the probable need for multiple treatments^94,95. This has been supported by others, showing that, despite a tumour /normal tissue fluorescence ratio of 5 : 1, a response rate of only 50% was obtained with a single ALA-PDT treatment⁷. Other small studies are summarized in Table 3^96-101. The optimal regimen for treatment has yet to be established.

Adverse effects

Acute
Pain or discomfort, often described as 'burning', 'stinging' or 'prickling' restricted to the illuminated area^102,103 is commonly experienced during ALA-PDT. It usually occurs in the early part of light exposure, peaking within minutes, then levelling out during the remainder of exposure, and probably reflects nerve stimulation and /or tissue damage by reactive oxygen species. This discomfort can occasionally persist for hours, and rarely for a few days, at a reduced intensity. Most patients will, however, tolerate topical ALA-PDT without anaesthesia/analgesia^38,46,57. Few clinical trials have carefully monitored pain, but the face and scalp may be more susceptible, and large and /or ulcerated lesions are more likely to be painful^28,44,56. Topical PDT of psoriasis and viral warts is frequently associated with pain (see above). While pain may be related to PDT dose, no linear relationship has been identified³⁷. Hyperthermia may contribute to tissue damage and thus intensify pain¹⁰⁴. The wave-length of light may influence pain severity, with green light less painful than red in a study of facial actinic keratoses³¹. Such difference in pain was, however, not noted in a randomised comparison of green and red light in Bowen's disease³².  Comparison studies indicate that the pain associated with ALA-PDT is less severe than that induced by cryotherapy and is equivalent to the total pain induced by topical 5-fluorouracil application^45,57,58,62.

Strategies to reduce pain include prior topical /injected local anaesthetic, premedication with benzodiazepine, cooling fans or spraying water on lesions during therapy^{48,52,56,61,102}. As ALA, but not ALA methylester, is transported by c-aminobutyric acid carriers, it is speculated that the ester might be less likely to provoke nerve fibre stimulation and hence pain¹⁰⁵. There remains no direct clinical comparison of these photosensitisers to test this hypothesis, nor of the different methods of alleviating pain.

Immediately following illumination, erythema and oedema are common, with erosion, crust formation and healing over 2-6 weeks^7,37,63,103. Unlike cryotherapy or topical 5-fluorouracil, ulceration following PDT is very rare^57,58.  No generalised photosensitivity has been reported following topical ALA-PDT in NMSC, and ALA-induced PpIX appears to be almost completely cleared from the body within 24h of its induction^16,106.

Chronic
A good cosmetic outcome following ALA-PDT is widely reported, regardless of lesion or site, in comparison with conventional therapy as supported by blinded clinical assessment⁶². A clinically obvious scar is rarely observed, although Fink-Puches et al. observed histological evidence of scarring⁶³. Hyperpigmentation or hypopigmentation can occasionally be seen in treated areas and usually resolves within 6 months, although prolonged hyperpigmentation was observed when treating hirsutism^{31,52,70,83,106}.

Permanent hair loss has been observed following ALA-PDT. In a patient with extensive scalp BCC, the local thinning over lesions was mild and much less than that following radiotherapy to an adjacent lesion107. Hair loss has been observed following ALA-PDT to large patches of Bowen's disease and BCC on non-scalp sites^52,56.

Carcinogenicity
PDT has the potential of promoting genotoxic effects, including induction of DNA strand breaks, chromosomal aberrations and alkylation of DNA^108-111. However, porphyrin molecules also possess antimutagenic properties, with ALA-PDT delaying photocarcinogenesis in mice¹¹². Following over 25 years of experimentation with PDT in humans, and 10 years of ALA-PDT, only two tumours have possibly been induced by this therapy^60,113. The first case concerns an 82-year-old man who had received, over 4 years, seven sessions of ALA-PDT to treat actinic keratoses and SCCs. Six months following his last treatment, a melanoma was identified at a site that had been included in four of the PDT sessions. Although possibly coincidental, there is the potential that repetitive treatments of PDT may have promoted its development. Recently, a 38-year-old man with erythroplasia of Queyrat appeared to have responded to ALA-PDT, with clearance on three post-therapy biopsies⁶⁰. Clinical doubt over completeness of clearance led to his commencement on topical 5-fluorouracil (twice weekly for 4 months), but an SCC was subsequently identified when a nodule developed on the penis. This case may represent simple progression of residual erythroplasia to SCC, but the possibility that PDT promoted this progression requires consideration. Overall, available evidence would indicate that the risk of skin cancer associated with topical PDT is low, but in view of the latent period for carcinogenesis, long-term follow-up data are required.

ALA-PDT has a low frequency of severe adverse effects, achieves a good cosmetic outcome, and has a low risk of carcinogenicity (strength of recommendation B, quality of evidence IIiii).

Safety aspects of topical photodynamic therapy

Topical PDT treatments are intrinsically very safe. The relative specificity of the photosensitiser to abnormal cells, taking some hours' application to be effective, and the use of lower energy radiation (normally in the visible spectrum), reduce the potential hazards. Accidental exposure to the photosensitiser carries a low risk, as washing removes it almost completely, and any residue is unlikely to be activated by normal environmental light levels.

Potential hazards may arise from the use of surgical lasers to deliver high-intensity light to photosensitised skin, and radiation in the blue, ultraviolet or infrared wavelengths may pose a greater potential hazard to skin and eyes. The lower energy visible radiation is much safer for the skin than ultraviolet, but there are potential hazards to the eye arising from the high intensities employed¹¹⁴. The retina is at risk from the photochemical hazard of blue light (400-450 nm), which could irreversibly damage the photosensitive neurotransmitters in the macula¹¹⁵. Most ALA-PDT is conducted at longer red bandwidths, but staff and patients are advised to wear suitable filter spectacles to limit the transmission of the high-intensity light, and to avoid discomfort and the disturbance of colour perception that can arise from intense exposure to a limited colour bandwidth.

Most radiation sources in use for dermatology presently are non-coherent incandescent or discharge lamps, but laser systems or LED arrays are sometimes used. Any laser system classified as class IIIb or IV (most medical lasers) is subject to the Laser Protection Guidelines. A certified Laser Protection Adviser should be consulted prior to the use of such a device. Modern LED devices have small source dimensions and high brilliance, but under normal conditions of use they should pose no significant increase in risk to the skin or eyes¹¹⁶.

Cost assessment of topical photodynamic therapy and comparison with existing therapy
In addition to clinical efficacy, assessment of cost-effectiveness is an important aspect of determining the overall benefit offered by a new therapy such as PDT. Such an assessment requires estimation of staff and equipment costs combined with number of treatments required, expectation for clearance, costs of associated morbidity, and diagnostic and follow-up requirements. Comparison of these figures with those from conventional therapy is limited by a deficiency of accurate data and difficulty placing a cost on certain outcome measures such as the relative superiority of PDT for good cosmesis. Estimated costs for treating patients with a single NMSC lesion with ALA-PDT are shown in Appendix 2. Medical staff time would be required for an initial clinic assessment and follow-up but as these are also required for the alternative treatment options, these costs have been omitted from the current calculations. Bell and Rhodes¹¹⁷ observed that up to eight visits (median 4) were required to clear lesions of Bowen's disease in 68 patients presenting to one UK dermatology department employing a range of treatment options other than PDT. An efficiently organized ALA-PDT service offers the potential for reducing the number of visits and hence the cost of managing this disease (Appendices 3, 4). Available estimates for cost-effectiveness indicate ALA-PDT to be generally comparable in cost with other therapies when morbidity costs in standard treatments are included, becoming more economical where multiple lesions can be treated in one irradiation field.

Conclusions

Many, typically open, uncontrolled studies indicate ALA-PDT to be effective in certain clinical applications (Appendix 5), particularly in actinic keratoses affecting the face and scalp, Bowen's disease and superficial BCC. Randomised comparison studies indicate PDT to be at least as effective as existing therapies for these indications. Cost effectiveness analysis suggests that with relatively cheap equipment costs, topical ALA-PDT is probably no more expensive than conventional therapy when its lower side-effect profile is considered. ALA is the predominant photosensitiser used. Early work indicates that its methyl ester derivative is also effective, although no comparison data exist. Several light sources are effective in delivering ALA-PDT. Certain lamps are more efficient at delivering the longer wavelengths considered optimal particularly for deeper lesions, although lack of direct comparison limits assessment of superiority. Contacts for photosensitiser and light sources are listed in Appendix 6.

ALA-PDT for non-hypertrophic actinic keratoses on the face and scalp and Metvix-PDT for BCC 'unsuitable for conventional therapy' is already approved (U.S.A. and Sweden), with European approvals in NMSC anticipated shortly. Caution is advised in considering topical PDT for thick/nodular BCC, unless with modifications such as adjunctive or fractionated therapy or for squamous cell carcinoma. Additional applications remain at the experimental stage, with early potential suggested in refractory warts and acne. We note that several large multi-centre studies on topical PDT with methyl-ALA and ALA are underway world-wide and are expected during the next 5 years to improve the quality of available evidence in specific indications.

Note added in proof

In December 2001, approval was granted for actinic keratoses and basal cell carcinomas in 14 European countries, including the UK for topical PDT using methyl 5-aminolevulinate-PDT (metvix ).

Acknowledgments

The authors thank LEO Pharmaceuticals for funding the workshop.

References

1 Kennedy JC, Pottier RH, Pross DC. Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experience. J Photochem Photobiol B Biol 1990; 6: 143-8.
2 Cox NH, Eady DJ, Morton CA. Guidelines for the management of Bowen's disease. Br J Dermatol 1999; 141: 633-41.
3 Telfer NR, Colver GB, Bowers PW. Guidelines for the management of basal cell carcinoma. Br J Dermatol 1999; 141: 415-23.
4 Ormrod D, Jarvis B. Topical aminolevulinic acid HCl photodynamic therapy. Am J Clin Dermatol 2000; 1: 133-9.
5 Henderson BW, Dougherty TJ. How does photodynamic therapy work? Photochem Photobiol 1992; 55: 145-57.
6 Dougherty TJ, Cooper MT, Mang TS. Cutaneous phototoxic occurrences in patients receiving photofrin. Lasers Surg Med 1990; 10: 485-8.
7 Svanberg K, Anderson T, Killander D et al. Photodynamic therapy of non-melanoma malignant tumours of the skin using topical 5-aminolaevulinic acid sensitisation and laser irradiation. Br J Dermatol 1994; 130: 743-51.
8 Santoro O, Banieramonte G, Melloni E et al. Photodynamic therapy by topical meso-tetraphenylporphinesulfonate tetrasodium salt administration in superficial basal cell carcinomas. Cancer Res 1990; 50: 4501-3.
9 Gupta G, Morton CA, Whitehurst C et al. Photodynamic therapy with mesotetra (hydroxyphenyl)chlorin in the topical treatment of Bowen's disease and basal cell carcinoma. Br J Dermatol 1999; 141: 385-6.
10 Wang I, Anderson-Ellis S, Nilsson GE et al. Superficial blood flow following photodynamic therapy of malignant non-melanoma skin tumours measured by laser Doppler perfusion imaging. Br J Dermatol 1997; 136: 184-9.
11 Pottier RH, Chow YFA, LaPlante JP et al. Non-invasive technique for obtaining fluorescence excitation and emission spectra in vivo. Photochem Photobiol 1986; 44: 679-87.
12 Szeimies R-M, Sassy T, Landthaler M. Penetration potency of topical applied 5-aminolaevulinic acid for photodynamic therapy of basal cell carcinoma. Photochem Photobiol 1994; 59: 73-6.
13 Martin A, Tope WD, Grevelink JM et al. Lack of selectivity of protoporphyrin IX fluorescence for basal cell carcinoma after topical application of 5-aminolevulinic acid: implications for photodynamic treatment. Arch Dermatol Res 1995; 287: 665-74.
14 Roberts DJH, Cairnduff F. Photodynamic therapy of primary skin cancer: a review. Br J Plast Surg 1995; 48: 360-70.
15 Hurlimann AF. Photodynamic therapy of superficial basal cell carcinomas using topical 5-aminolevulinic acid in a nanocolloid lotion. Dermatology 1998; 197: 248-54.
16 Rhodes LE, Tsoukas MM, Anderson RR, Kollias N. Iontophoretic delivery of ALA provides a quantitative model for ALA pharmacokinetics and PpIX phototoxicity in human skin. J Invest Dermatol 1997; 108: 87-91.
17 Peng Q, Warloe T, Moan J et al. Distribution of 5-aminolevulinic acid-induced porphyrins in noduloulcerative basal cell carcinoma. Photochem Photobiol 1995; 62: 906-13.
18 Harth Y, Hirschowitz B, Kaplan B. Modified topical photodynamic therapy of superficial skin tumors, utilizing aminolevulinic acid, penetration enhancers, red light and hyperthermia. Dermatol Surg 1998; 24: 723-6.
19 Orenstein A, Kostenich G, Roitman L et al. Photodynamic therapy of malignant lesions of the skin mediated by topical application of 5-aminolevulinic acid in combination with DMSO and EDTA. Lasers Life Sci 1996; 7: 1-9.
20 Fijan S, Honigsmann H, Ortel B. Photodynamic therapy of epithelial skin tumours using delta-aminolaevulinic acid and des-ferrioxamine. Br J Dermatol 1995; 133: 282-8.
21 Warloe T, Heyerdahl H, Peng Q, Giercksky K-E. Photodynamic therapy with 5-aminolaevulinic acid induced porphyrins and skin penetration enhancer for basal cell carcinoma. SPIE 1994; 2371: 226-35.
22 Thissen MR, Schroeter CA, Neumann HA. Photodynamic therapy with delta-aminolaevulinic acid for nodular basal cell carcinomas using a prior debulking technique. Br J Dermatol 2000; 142: 338-9.
23 Gerscher S, Connelly JP, Griffiths J et al. Comparison of the pharmacokinetics and phototoxicity of protoporphyrin IX metabolised from 5-aminolevulinic acid and two derivatives in human skin in vivo. Photochem Photobiol 2000; 72: 569-74.
24 Gerscher S, Connelly JP, Beijersbergen van Henegouwen GMJ et al. A quantitative assessment of protoporphyrin IX metabolism and phototoxicity in human skin following dose-controlled delivery of the prodrugs 5-aminolaevulinic acid and 5-amino-laevulinic acid-n-pentylester. Br J Dermatol 2001; 144: 983-90.
25 Braathen L, Paredes B, Fro¨ lich K et al. A dose-finding study of photodynamic therapy (PDT) with Metvix TM in actinic keratoses (AK). J Eur Acad Dermatol Venereol 2000; 14 (Suppl. 1): 38.
26 Basset-Seguin N, Bachmann I, Pavel S et al. A dose-finding study of photodynamic therapy (PDT) with Metvix TM in patients with basal cell carcinoma (BCC). J Eur Acad Dermatol Venereol 2000; 14 (Suppl. 1): 39.
27 Horn M, Larko¨ O, Wulf HC et al. Photodynamic therapy (PDT) with Metvix cream 160 mg /g in patients with basal cell carcinoma (BCC) unsuitable to conventional therapy. Presented at the Society for Investigative Dermatology, Washington DC, 2001.
28 Morton CA, MacKie RM, Whitehurst C et al. Photodynamic therapy for basal cell carcinoma: effect of tumor thickness and duration of photosensitiser application on response. Arch Dermatol 1998; 134: 248-9.
29 Soler AM, Angell-Petersen E, Warloe T et al. Photodynamic therapy of superficial basal cell carcinoma with 5-aminolaevu-linic acid with dimethylsulphoxide and ethylendiaminetetra-acetic acid: a comparison of two light sources. Photochem Photobiol 2000; 71: 724-9.
30 Gudgin Dickson EF, Pottier RH. On the role of protoporphyrin IX photoproducts in photodynamic therapy. J Photochem Photobiol B Biol 1995; 29: 91-3.
31 Fritsch C, Stege H, Saalmann G et al. Green light is effective and less painful than red light in photodynamic therapy of facial solar keratoses. Photodermatol Photoimmunol Photomed 1997; 13: 181-5.
32 Morton CA, Whitehurst C, Moore JV, MacKie RM. Comparison of red and green light in the treatment of Bowen's disease by photodynamic therapy. Br J Dermatol 2000; 143: 767-72.
33 Moseley H. Total effective fluence: a useful concept in photodynamic therapy. Lasers Med Sci 1996; 11: 139-43.
34 Peng Q, Warloe T, Berg K et al. 5-ALA based photodynamic therapy. Cancer 1997; 79: 2282-308.
35 Svaasand LO. Photodynamic and photohyperthermic response of malignant tumours. Med Phys 1985; 12: 455-61.
36 Langmack K, Mehta R, Twyman P, Norris P. Topical photodynamic therapy at low fluence rates-theory and practice. J Photochem Photobiol B Biol 2001; 60: 37-43.
37 Collins P, Robinson DJ, Stringer MR et al. The variable response of plaque psoriasis after a single treatment with topical 5-aminolaevulinic acid photodynamic therapy. Br J Dermatol 1997; 137: 743-9.
38 Wolf P, Rieger E, Kerl H. An alternative treatment modality for solar keratoses, superficial squamous cell carcinomas and basal cell carcinomas? J Am Acad Dermatol 1993; 28: 17-21.
39 Szeimies R-M, Karrer S, Sauerwald A, Landthaler M. Photodynamic therapy with topical application of 5-aminolaevulinic acid in the treatment of actinic keratoses: an initial clinical study. Dermatology 1996; 192: 246-51.
40 Jeffes EW, McCullough JL, Weinstein GD et al. Photodynamic therapy of actinic keratoses with topical 5-aminolaevulinic acid. Arch Dermatol 1997; 133: 727-32.
41 Karrer S, Baumler W, Abels C et al. Long-pulse dye laser for photodynamic therapy. Lasers Surg Med 1999; 25: 51-9.
42 Stefanidou M, Tosca A, Themelis G et al. In vivo fluorescence kinetics and photodynamic therapy efficacy of delta-aminolevulinic acid-induced porphyrins in basal cell carcinomas and actinic keratoses; implications for optimization of photodynamic therapy. Eur J Dermatol 2000; 10: 351-6.
43 Itoh Y, Ninomiya T, Henta T et al. Topical 5-aminolaevulinic acid-based photodynamic therapy for Japanese actinic keratoses. J Dermatol 2000; 27: 513-18.
44 Fink-Puches R, Hofer A, Smolle J et al. Primary clinical response and long-term follow-up of solar keratoses treated with topically applied 5-aminolaevulinic acid and irradiation by different wave bands of light. J Photochem Photobiol B Biol 1997; 41: 145-51.
45 Kurwa HA, Yong-Gee SA, Seed PT et al. A randomized paired comparison of photodynamic therapy and topical 5-fluorouracil in the treatment of actinic keratoses. J Am Acad Dermatol 1999; 41: 414-18.
46 Calzavara-Pinton PG. Repetitive photodynamic therapy with topical 5-aminolaevulinic acid as an appropriate approach to the routine treatment of superficial non-melanoma skin tumours. J Photochem Photobiol B Biol 1995; 29: 53-7.
47 Szeimies R-M, Radakovic S, Calzavara-Pinton PG et al. A prospective, randomized study comparing photodynamic therapy with Metvix , to cryotherapy in actinic keratoses. J Eur Acad Dermatol Venereol 2000; 14 (Suppl. 1): 235.
48 Cairnduff F, Stringer MR, Hudson EJ et al. Superficial photodynamic therapy with topical 5-aminolaevulinic acid for superficial primary and secondary skin cancer. Br J Cancer 1994; 69: 605-8.
49 Lui H, Salasche S, Kollias N et al. Photodynamic therapy of non-melanoma skin cancer with topical aminolaevulinic acid: a clinical and histologic study. Arch Dermatol 1995; 131: 737-8.
50 Morton CA, Whitehurst C, Moseley H et al. Development of an alternative light source to lasers for photodynamic therapy: clinical evaluation in the treatment of pre-malignant non-melanoma skin cancer. Lasers Med Sci 1995; 10: 165-71.
51 Wennberg A, Lindholm L, Alpsten M et al. Treatment of basal cell carcinomas using topically applied delta-aminolaevulinic acid and a filtered xenon lamp. Arch Dermatol Res 1996; 288: 561-4.
52 Stables GI, Stringer MR, Robinson DJ, Ash DJ. Large patches of Bowen's disease treated by topical aminolaevulinic acid photodynamic therapy. Br J Dermatol 1997; 136: 957-60.
53 Fritsch C, Goerz G, Ruzicka T. Photodynamic therapy in dermatology. Arch Dermatol 1998; 134: 207-14.
54 Mehta RK, Levell NJ, Langmack K, Norris PG. Low intensity light photodynamic therapy (PDT) using a novel 635 nm light source is effective in Bowen's disease. Br J Dermatol 2001; 145 (Suppl. 59): 54-5 (Abstr.).
55 Varma S, Wilson H, Kurwa HA et al. Bowen's disease, solar keratoses and superficial basal cell carcinomas treated by photodynamic therapy using a large-field incoherent light source. Br J Dermatol 2001; 144: 567-74.
56 Morton CA, Whitehurst C, McColl JH et al. Photodynamic therapy for large or multiple patches of Bowen's disease and basal cell carcinoma. Arch Dermatol 2001; 137: 319-24.
57 Morton CA, Whitehurst C, Moseley H et al. Comparison of photodynamic therapy with cryotherapy in the treatment of Bowen's disease. Br J Dermatol 1996; 135: 766-71.
58 Salim A, Morton CA. Comparison of photodynamic therapy with topical 5-fluorouracil in Bowen's disease. Br J Dermatol 2000; 114 (Suppl. 57): 114 (Abstr.).
59 Stables GI, Stringer MR, Robinson DJ, Ash DV. Erythroplasia of Queyrat treated by topical aminolaevulinic acid photodynamic therapy. Br J Dermatol 1999; 140: 514-17.
60 Varma S, Holt PJA, Anstey AV. Erythroplasia of Queyrat treated by topical aminolaevulinic acid photodynamic therapy: a cautionary tale. Br J Dermatol 2000; 142: 825-6.
61 Soler AM, Warloe T, Tausjo J, Berner A. Photodynamic therapy by topical aminolaevulinic acid, dimethylsulphoxide and curettage in nodular basal cell carcinoma: a one year follow-up study. Acta Derm Venereol (Stockh) 1999; 79: 204-6.
62 Wang I, Bendsoe N, Klinteberg CAF et al. Photodynamic therapy vs. cryosurgery of basal cell carcinomas: results of a phase III clinical trial. Br J Dermatol 2001; 144: 832-40.
63 Fink-Puches R, Soyer HP, Hofer A et al. Long-term follow-up and histological changes of superficial non-melanoma skin cancers treated with topical delta-aminolevulinic acid photodynamic therapy. Arch Dermatol 1998; 134: 821-6.
64 Haller JC, Cairnduff F, Slack G et al. Routine double treatments of superficial basal cell carcinomas using aminolaevulinic acid-based photodynamic therapy. Br J Dermatol 2000; 143: 1270-4.
65 Stender IM, Wulf HC. Photodynamic therapy with 5-aminolaevulinic acid in the treatment of actinic cheilitis. Br J Dermatol 1996; 135: 454-6.
66 Frank RG, Bos JD, Meulen FW, Sterenborg HJ. Photodynamic therapy for condylomata acuminata with local application of 5-aminolaevulinic acid. Genitourin Med 1996; 72: 70-1.
67 Hillemanns P, Untch M, Prove F et al. Photodynamic therapy of vulvar lichen sclerosus with 5-aminolaevulinic acid. Obstet Gynecol 1999; 93: 71-4.
68 Karrer S, Abels C, Landthaler M, Szeimies R-M. Topical photodynamic therapy for localized scleroderma. Acta Derm Venereol (Stockh) 2000; 80: 26-7.
69 Karrer S, Szeimies R-M, Abels C et al. Epidermodysplasia verruciformis treated using topical 5-aminolaevulinic acid photodynamic therapy. Br J Dermatol 1999; 140: 935-8.
70 Grossman M, Wimberly J, Dwyer P et al. PDT for hirsutism. Lasers Surg Med 1995; 7 (Suppl.): 44.
71 Kirby B, Whitehurst C, Moore JV, Yates VM. Treatment of lichen planus of the penis with photodynamic therapy. Br J Dermatol 1999; 141: 747-76.
72 Dierickx CC, Goldenhersh M, Dwyer P et al. Photodynamic therapy for nevus sebaceus with topical d-aminolaevulinic acid. Arch Dermatol 1999; 135: 637-40.
73 Martin-Hirsch PL, Whitehurst C, Moseley H et al. Photodynamic therapy for lower genital tract intra-epithelial neoplasia. Lancet 1998; 351: 1403.
74 Hillemans P, Untch M, Danneker C et al. Photodynamic therapy of vulval intra-epithelial neoplasia using 5-aminolaevulinic acid. Int J Cancer 2000; 85: 649-53.
75 Kurwa HA, Barlow RJ, Neill S. Single-episode photodynamic therapy and vulval intraepithelial neoplasia type III resistant to conventional therapy. Br J Dermatol 2000; 143: 1040-2.
76 Zollo JD, Zeitouni NC. The Roswell Park Cancer Institute experience with extramammary Paget's disease. Br J Dermatol 2000; 142: 59-65.
77 Henta T, Itoh Y, Kobayashi M et al. Photodynamic therapy for inoperable vulval Paget's disease using d-aminolaevulinic acid: successful management of a large skin lesion. Br J Dermatol 1999; 141: 347-9.
78 Bissonnette R, Shapiro J, Zeng H et al. Topical photodynamic therapy with 5-aminolaevulinic acid does not induce regrowth in patients with extensive alopecia. Br J Dermatol 2000; 143: 1032-5.
79 Ammann R, Hunziker T, Braathen LR. Topical photodynamic therapy in verrucae. A pilot study. Dermatology 1995; 191: 346-7.
80 Stender IM, Wulf CH. Treatment of recalcitrant verrucae by photosensitivity with topical application of d-aminolaevulinic acid. Clin Exp Dermatol 1996; 21: 390.
81 Stender IM, Lock-Anderson J, Wulf HC. Recalcitrant hand and foot warts successfully treated with photodynamic therapy with topical 5-aminolaevulinic acid: a pilot study. Clin Exp Dermatol 1999; 24: 154-9.
82 Stender IM, Wulf HC. Photodynamic therapy of recalcitrant warts with 5-aminolaevulinic acid: a retrospective analysis. Acta Derm Venereol (Stockh) 1999; 79: 400-1.
83 Stender IM, Na R, Fogh H et al. Photodynamic therapy with 5-aminolaevulinic acid or placebo for recalcitrant foot and hand warts: randomised double-blind trail. Lancet 2000; 355: 963-6.
84 Papageorgiou P, Katsambas A, Chu A. Phototherapy with blue (415 nm) and red (660 nm) light in the treatment of acne vulgaris. Br J Dermatol 2000; 142: 973-8.
85 Hongcharu W, Taylor CR, Chang Y et al. Topical ALA-photodynamic therapy for the treatment of acne vulgaris. J Invest Dermatol 2000; 115: 183-92.
86 Itoh Y, Ninomiya Y, Tajima S, Ishibashi A. Photodynamic therapy for acne vulgaris with topical 5-aminolaevulinic acid. Arch Dermatol 2000; 136: 1093-5.
87 Itoh Y, Ninomiya Y, Tajima S, Ishibashi A. Photodynamic therapy of acne vulgaris with topical 5-aminolaevulinic acid and incoherent light in Japanese patients. Br J Dermatol 2001; 144: 575-9.
88 Boehncke W-H, Konig K, Kaufmann R et al. Photodynamic therapy in psoriasis: suppression of cytokine production in vitro and recording of fluorescence modification during treatment in vivo. Arch Dermatol Res 1994; 286: 300-3.
89 Boehncke W-H, Sterry W, Kaufmann R. Treatment of psoriasis by topical photodynamic therapy with polychromatic light. Lancet 1994; 343: 801.
90 Weinstein GD, McCullough JL, Jeffes EW et al. Photodynamic therapy (PDT) of psoriasis with topical delta aminolevulinic acid (ALA): a pilot dose-ranging study. Photochem Photobiol Photo-immunol 1994; 10: 92.
91 Stringer MR, Collins P, Robinson DJ et al. The accumulation of protoporphyrin IX in plaque psoriasis after topical application of 5-aminolaevulinic acid indicates a potential for superficial photodynamic therapy. J Invest Dermatol 1996; 107: 76-81.
92 Robinson DJ, Collins P, Stringer MR et al. Improved response of plaque psoriasis after multiple treatment with topical 5-aminolaevulinic acid photodynamic therapy. Acta Derm Venereol (Stockh) 1999; 79: 451-5.
93 Boehncke W-H, Konig K, Ruck A et al. In vitro and in vivo effect of photodynamic therapy in cutaneous T cell lymphoma. Acta Derm Venereol (Stockh) 1994; 74: 201-5.
94 Wolf P, Fink-Punches R, Cerroni L, Kerl H. Photodynamic therapy for mycosis fungoides after topical photosensitization with 5-aminolaevulinic acid. J Am Acad Dermatol 1994; 31: 678-80.
95 Ammann R, Hunziker R. Photodynamic therapy for mycosis fungoides after topical photosensitization with 5-aminolevulinic acid. J Am Acad Dermatol 1995; 33: 541.
96 Oseroff AR, Whitaker J, Conti C et al. Effects of fluence and intensity in PDT of cutaneous T-cell lymphoma with topical ALA: high intensities spare the epidermis. J Invest Dermatol 1996; 106: 950.
97 Stables GI, Stringer MR, Robinson DJ. The treatment of cutaneous T-cell lymphoma by topical aminolaevulinic acid photodynamic therapy. Br J Dermatol 1997; 137 (Suppl. 50): 50.
98 Edstrom DW, Ros AM, Parvit A. Topical 5-aminolaevulinic acid based photodynamic therapy for mycosis fungoides-a study of cell proliferation and apoptosis before and after therapy. J Dermatol Sci 1998; 16: 229.
99 Wang I, Bauer B, Andersson-Engels S et al. Photodynamic therapy utilising topical delta-aminolaevulinic acid in non-melanoma skin malignancies of the eyelid and the periocular skin. Acta Ophthalmol Scand 1999; 77: 182-8.
100 Markham T, Sheahan K, Collins P. Topical 5-aminolaevulinic acid photodynamic therapy for tumour stage mycosis fungoides. Br J Dermatol 2001; 144: 1262-3.
101 Orenstein A, Haik J, Tamir J et al. Photodynamic therapy of cutaneous lymphoma using 5-aminolaevulinic acid topical application. Dermatol Surg 2000; 26: 765-70.
102 Lui H, Anderson RR. Photodynamic therapy in dermatology; recent developments. Dermatol Clin 1993; 11: 1-13.
103 Kalka K, Merk H, Mukhtar H. Photodynamic therapy in dermatology. J Am Acad Dermatol 2000; 42: 389-413.
104 Orenstein A, Kostenick G, Taur H et al. Temperature monitoring during photodynamic therapy of skin tumours with topical 5-aminolaevulinic acid application. Cancer Lett 1995; 93: 227-32.
105 Rud E, Gederaas O, Hogset A, Berg K. 5-aminolaevulinic acid, but not 5-aminolaevulinic acid esters, is transported into adenocarcinoma cells by system BETA transporters. Photochem Photobiol 2000; 71: 640-7.
106 Kennedy JC, Pottier RH. Endogenous protoporphyrin IX, a clinically useful photosensitizer for photodynamic therapy. J Photochem Photobiol B Biol 1992; 14: 275-92.
107 Morton CA, Burden AD. Treatment of multiple scalp basal cell carcinomas by photodynamic therapy. Clin Exp Dermatol 2001; 26: 33-6.
108 Moan J, Waksvik H, Christensen T. DNA single stranded breaks and sister chromatid exchanges induced by treatment with hematoporphyrin and light or by X-rays in human NHIK 3025 cells. Cancer Res 1980; 40: 2915-18.
109 Fiedler DM, Eckl PM, Krammer B. Does d-aminolaevulinic acid induce genotoxic effects? J Photochem Photobiol B Biol 1996; 33: 39-44.
110 Douki T, Onuki J, Medeiros MGH et al. DNA alkylation by 4,5-dioxovaleric acid, the final oxidation product of 5-aminolevulinic acid. Chem Res Toxicol 1998; 11: 150-7.
111 Fuchs J, Weber S, Kaufmann R. Genotoxic potential of porphyrin type photosensitizers with particular emphasis on 5-aminolevulinic acid: implications for clinical photodynamic therapy. Free Rad Biol Med 2000; 28: 537-48.
112 Stender IM, Bech-Thomsen N, Poulsen T, Wulf HC. Photodynamic therapy with topical delta-aminolevulinic acid delays UV photocarcinogenesis in hairless mice. Photochem Photobiol 1997; 66: 493-6.
113 Wolf P, Fink-Puches R, Reimann-Weber A, Kerl H. Development of malignant melanoma after repeated topical photodynamic therapy with 5-aminolevulinic acid at the exposed site. Dermatology 1997; 194: 53-4.
114 Commission Internationale de l'E ` clairage (CIE). Photobiological Safety Standards for Lamps. Report of TC6-38; CIE 134-3-99. Vienna: CIE, 1999.
115 Ham WT. The photopathology and nature of the blue-light and near-UV retinal lesion produced by lasers and other optical sources. In: Laser Applications in Medicine and Biology (Wolbarsht ML, ed.). New York: Plenum Press, 1989; 191-246.
116 Matthes R. for the International Commission on Non-Ionising Radiation Protection. ICNIRP statement on light-emitting diodes (LEDS) and laser diodes: implications for hazard assessment. Health Phys 2000; 78: 744-52.
117 Bell HK, Rhodes LE. Bowen's disease-a retrospective review of clinical management. Clin Exp Dermatol 1999; 24: 336-7.
118 The new National Health Service. Reference costs 2000--Appendix 1-National schedule for reference costs. Dermatology Out-patient Healthcare Resource Groups. Available from http://www.doh.gov.uk/nhsexec/refcosts.htm.
119 Williams HC. Prevalence of non-melanoma skin cancer. In: Health Care Needs Assessment-Dermatology (Stevens A, Raftery J, eds), 2nd edn. Oxford: Radcliffe Medical Press, 1997; 66-8.

Appendix 1: Strength of recommendations and quality of evidence

Strength of recommendations
A There is good evidence to support the use of the procedure.
B There is fair evidence to support the use of the procedure.
C There is poor evidence to support the use of the procedure.
D There is fair evidence to support the rejection of the use of the procedure.
E There is good evidence to support the rejection of the use of the procedure.

Quality of evidence
I Evidence obtained from at least one properly designed, randomized controlled trial.
IIi Evidence obtained from well-designed controlled trials without randomization.
IIii Evidence obtained from well-designed cohort or case-control analytical studies, preferably from more than one centre or research group.
IIiii Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments could also be regarded as this type of evidence.
III Opinions of respected authorities based on clinical experience, descriptive studies or reports of expert committees.
IV Evidence inadequate owing to problems of methodology.

Appendix 2: Cost comparison of topical 5-aminolaevulinic acid-photodynamic therapy (ALA-PDT) with standard therapy

Estimated for a patient presenting to the U.K. National Health Service, with a 2 x 2 cm plaque of Bowen's disease. Based on published clearance/morbidity rates^57,58 with average costs derived from out-patient healthcare resource group codes¹¹⁸.
1 ALA-PDT: £119 (assumes two treatments to clear 25% of lesions + 4% recurrence rate with clearance on repeat treatment). Single therapy cost breakdown:

(a) Light: £53 (averaged cost of the two sources most widely reported in the literature: (i) Paterson PTL, leased and using smartcard: £80 per lesion; (ii) Waldmann 1200: cost £11697, maintenance £400 per year for years 2-5, excluding replacement of filter + lamp at 500h @£ 2444, assuming 5-year life and use to clear 100 lesions per year: £27 per lesion).

(b) Photosensitizer: £24 (£70 for 4.5g Porphin cream, three lesions per tube possible if multiple lesions are treated each day and measures taken to avoid cross-infection).

(c) Nursing: £10 (grade E, 1h).

(d) Consumables: £5 (dressings, local anaesthesia etc.) ¼Total: £92 per single treatment.

2 Cryotherapy: £145 @ £64 per treatment, 50% of lesions require two or three treatments and 10% recurrence (assuming one successful re-treatment). Estimated 'complication' cost to cover ulceration and /or infection rate of 25% assumes one additional dressing visit @ £68 and one extra review visit @ £50 per complication but excludes district nurse/general practitioner visit costs and dressing/topical therapy cost for each complication)⁵⁷.

3 Topical 5-fluorouracil: £171 @ £68 per treatment cycle (£50 per visit + £18 for topical 5-fluorouracil), 33% clear on one cycle, 30% on two, 30% failures (assume then cleared with single cryotherapy), 27% recurrence rate (assume then clear with one further cycle), complication rate (including ulceration and severe dermatitis) of 30% at same cost per complication as cryotherapy)⁵⁸.

Appendix 3: Outline protocol for topical 5-aminolaevulinic acid-photodynamic therapy (ALA-PDT) in non-melanoma skin cancer

1 Out-patient assessment: record diagnosis (consider biopsy and photography), number, size and site of lesions, additional medical diseases and current medication, required treatment regimen (photosensitiser duration, single/double treatment).

2 Provision of patient with information sheet and consent in clinic or at treatment.

3 Attendance to dermatology treatment unit for lesion preparation (e.g. removing crusts with gauze soaked in saline, with or without forceps) and application of ALA preparation, including 5-mm margin around lesion. Application of an adhesive dressing to retain cream at site (e.g. Tegaderm, 3M, Loughborough, U.K.) plus a dressing to minimize ambient light exposure (e.g. Mepore, Molnlycke Health Care, Sweden).

4 Patient then returns 4-6h later, for removal of excess cream and optional check of surface fluorescence with an ultraviolet Woods' lamp (e.g. UVL-56, Upland, CA, U.S.A.)-helpful in confirming protoporphyrin IX generation at least in superficial part of lesion.

5 Option for either pretreatment application of a topical anaesthetic, e.g. EMLA cream (Astra, King's Langley, U.K.), applied following removal of excess ALA 1h prior to illumination (i.e. at 3-5h), or provision during illumination, if required, of local injected anaesthesia, e.g. 1-2% lignocaine (plain suggested to minimize possible vasoconstricting effects of adrenaline on PDT efficacy).

6 Illumination of lesion to a lamp-specific protocol, with illumination field including a border around each lesion of at least 5 mm. Ensure that the correct position of light is maintained. Total light dose and intensity of illumination should be recorded.

7 Protect treatment site from ambient light for up to 24-48h.

Appendix 4: Setting up a topical photo-dynamic therapy (PDT) service (preparing the business case)

1 Define the clinical need: estimation of number of suitable patients and current management approach, taking into consideration rising non-melanoma skin cancer prevalence, complications and patient perceptions of existing therapies; local audit and pathology data helpful^117,119.

2 Describe topical PDT and its uses, its potential advantages over existing therapies, including estimated savings (e.g. reduced ulceration).

3 Include protocol and description of patient journey if new service implemented.

4 Costing PDT:

(a) Site (dedicated room vs. sharing out-patient treatment centre facilities, specific adaptations if laser source considered).

(b) Staffing: (i) medical (supervision of service, but low real-time requirement other than diagnostic and follow-up visits if performed to protocol, with clinic referral to day/phototherapy unit); (ii) nursing (hours of dermatology nurse specialist time-grade to depend on local expertise, but ability to perform entire procedure, including local anaesthesia, if required, preferable); (iii) medical records (appointments, case records-potential for similar set-up to other phototherapies).

(c) Equipment: (i) light source (purchase vs. lease, maintenance costs); (ii) photosensitiser (cost per lesion vs. drug unit cost); (iii) disposables, e.g. dressings.

5 Training: time required and arrangements proposed for training staff to become competent in PDT.

6 Proposals for prospective audit of new service.

Appendix 5: Strength of recommendations and quality of evidence assessment

A-IIiii A range of light sources is effective in promoting dermatological applications of 5-aminolaevulinic acid-photodynamic therapy (ALA-PDT).
B-IIiii Topical ALA-PDT is a safe treatment with few side-effects and no evidence of carcinogenicity during a decade of clinical use.
A-I Actinic keratoses (non-hyperkeratotic, face and scalp).
A-I Bowen's disease (squamous cell carcinoma in situ).
A-I Superficial basal cell carcinoma (BCC) (thickness < 2 mm).
B-I Acne.
B-I Warts.
C-IIiii Thick/nodular BCC
C-IIiii Cutaneous T-cell lymphoma.
C-IIiii Cutaneous metastases of breast carcinoma.
C-IIiii Psoriasis.
C-IIiii Vulval intraepithelial neoplasia.
D-I Alopecia areata.
D-IIiii Squamous cell carcinoma.

Appendix 6: Contacts for photosensitiser [5-aminolaevulinic acid (ALA)] and light sources

ALA (Porphin ): Crawford Pharmaceuticals, Furtho House, 20 Towcester Road, Old Stratford, Milton Keynes MK19 6AQ, U.K.

ALA (Levulan Kerastick and Blu-U lamp): registered to DUSA Pharmaceuticals, Inc., Wilmington, MA, U.S.A. European contact: Schering AG, Centre of Dermatology, D-13342 Berlin, Germany.

ALA-methylester (Metvix ): Photocure ASA, Hoffsvn. 48, N-0377 Oslo, Norway. Outside Nordic countries, contact: Galderma SA, Tour Europlaza, La Defence 4, 20 avenue Andre Prothin, F-92927, La Defence cedex, France.

Paterson Lamp: Phototherapeutics Ltd, Station Business Centre, Station House, Stamford New Road, Altrincham, Greater Manchester WA14 1EP, U.K.

Light-emitting diode source: PRP Optoelectronics Ltd, Wood Burcote Way, Towcester NN12 7HT, U.K.

Waldmann PDT 1200 light source: Waldmann, U.K., c /o Athrodax, Great Western Court, Ross-on-Wye HR9 7XP, U.K. or Peter-Henlein-Strasse 5, D-78056 Villingen-Schwennigen, Germany.