Treating basal cell carcinoma: has photodynamic therapy come of age?

Photodynamic therapy (PDT) involves the activation of a photosensitizing drug by visible light to produce activated oxygen species which promote tumour destruction.1 Despite a rising tide of publications in recent years, PDT was first described 100 years ago. Generalized and severe phototoxicity from early crude photosensitizers limited development, although partial purification produced a haematoporphyrin derivative, with the first human trial, which included basal cell carcinomas, performed almost 25 years ago. However, generalized photosensitivity could persist for up to 8 weeks, a strong deterrent to dermatological applications for which alternative therapies existed, although the commercial, partly purified formulation, Photofrin®, has been approved in several countries for early and advanced pulmonary and oesophageal cancer. The use of a topically effective agent, 5‐aminolaevulinic acid (5‐ALA), has triggered the current wave of enthusiasm towards PDT. Exogenous 5‐ALA increases the intracellular production of the endogenous photosensitizer protoporphyrin IX, via the haem pathway, with preferential accumulation in neoplastic tissue.1 Topical ALA–PDT appears particularly effective in actinic keratoses of the face and scalp, and in Bowen's disease, where advantages over conventional therapy regarding adverse events and cosmesis have been demonstrated.2,3 Published clearance rates for ALA–PDT in basal cell carcinomas (BCCs) range from 79 to 100% for clinically superficial lesions and 10–75% for nodular lesions, with lesions less than 2 mm thick on diagnostic biopsy achieving a superior outcome.2,4 Examination of the fluorescence emitted by ALA‐induced PpIX has shown full thickness fluorescence in 6/7 superficial and 4/9 nodular BCCs after 20% ALA application and partial superficial fluorescence in the five remaining nodular BCCs.5 A complete clearance rate (CCR) of 96% at 12 months for superficial BCCs has demonstrated the importance of technique, with two treatments 7 days apart yielding results superior to the same group's 50% CCR after a single treatment.6 Two other topically active photosensitizers have been evaluated. Topical meso‐tetraphenylporphinesulphonate tetrasodium (mTPPS) cleared 94% of 292 superficial BCCs on a single treatment with a 10% recurrence rate.7 Topical meta‐tetrahydroxyphenylchlorin (mTHPC) has also been assessed in a pilot study in Bowen's disease and superficial BCC, but with disappointing results, achieving histological clearance rates of 32% and 29%, respectively, suggesting that systemic application may be required.8 Baas et al.9 in this issue describe a phase I/II study of PDT using systemic mTHPC to treat 187 lesions in five patients with multiple superficial BCCs, including two with naevoid basal cell carcinoma syndrome. A light‐emitting diode device was employed and treatment times ranged from 50 to 150 s, with complete response rates at 12 months of up to 86%. Photosensitivity limited patients to subdued lighting conditions for 1 week and restrictions on sunlight exposure for a second week. mTHPC can achieve tumour necrosis to a depth of 1 cm with red light at 652 nm suggesting that even thick nodular BCC might be effectively targeted. Systemic mTHPC‐PDT might thus be best developed for nodular and/or multiple BCC, where topical ALA‐PDT is limited in efficacy and practicality, although restrictions on light exposure will remain a concern for patient and doctor. Other second generation photosensitisers, e.g. benzoporphyrin derivative‐monoacid, are likely also to be evaluated for these indications. The challenge to the dermatologist remains to optimize outcomes following topical PDT. Soler et al.10 have reported the clearance of 92% of 119 nodular BCC ≥ 2 mm thick following debulking curettage prior to ALA–PDT (also using dimethylsulphoxide). Improving penetration of 5‐ALA may also be achieved by rendering the molecule more lipophilic by esterification. A dose‐finding study of methyl 5‐ALA has achieved clearance rates of up to 90% for nodular BCC although lesion preparation included a shave of the superficial part of lesions.11 Interpretation of the success of a therapy is limited by the understandable trend in studies to minimize the requirement for histologicial confirmation of clearance, in particular in BCC, due to their typically indolent nature. Wang et al.,12 in a recent BJD article, reported the first randomized comparison study of ALA–PDT with cryotherapy for both superficial and nodular BCC, with no significant difference in response, although with fewer adverse events, shorter healing times and superior cosmesis following PDT. Recurrence rates at 12 months, by clinical examination, were 5% after PDT and 13% following cryotherapy, but 25% and 15%, respectively, when verified by histopathology at the same visit. The observation of late recurrence in BCC is not new. Rowe et al.13 observed in a meta‐analysis of conventional therapies, pre‐PDT, that where 10 years' follow‐up data was available, only 30% recurrences arose in the first year. After 5 years, 82% of recurrences had occurred, with rates ranging from 7·5% to 10·1%, for all modalities except Mohs' (1%). A practical compromise would be to insist that all clinical trials of the outcome of BCC therapies, where histopathological proof of clearance is not pursued, should be over a minimum of 2 years during which 50% recurrence would be expected to occur. Long‐term follow‐up data in this journal14 indicates an overall 9% recurrence rate after 45 months (16–73 months) for ALA–PDT in superficial BCC in lesions 24–3250 mm2. Regulatory authorities and the editors of journals should also encourage the publication of supplementary long‐term follow‐up reports in all therapeutic interventions. The evolution of PDT exemplifies the requirement to achieve a rolling programme to update BAD guidelines, with 15 studies of PDT in BCC and five on other BCC treatments on Medline since the guidelines on BCC were published in 1999.15 Following FDA approval for ALA‐PDT for actinic keratoses in 2000, European approval is anticipated for topical PDT in AK and BCC. Has PDT come of age in BCC? Refinements in photosensitizer and light dosimetry seem likely to achieve reproducible high response rates for superficial BCC. Patients with large and multiple lesions may benefit particularly, especially those lesions in challenging anatomical sites.16 The inconsistent clearance rates published to date suggest that typical thick nodular BCC should not be treated by PDT, unless assisted by curettage, penetration enhancers and/or repeated treatments. The presence of small nests of BCC cells in lesions judged clear on inspection following a therapy such as ALA–PDT, known to be limited in efficacy by tumour thickness, indicates the need for long‐term follow‐up study and challenges us to not interpret clear as cure.