The Use of Photodynamic Therapy as Chemoprevention for the Treatment of Actinic Keratoses and Reduction in the Number of Non-Melanoma Skin Cancers

Actinic keratoses (AKs) and superficial non-melanoma skin cancers (NMSCs), such as basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs), are commonly encountered skin conditions. AK is a precancerous skin condition with over 800,000 new cases being reported annually in the US. In immunocompetent subjects, it is reported that the incidence of AKs evolving into skin cancers in 5 to 10 years is between 5 – 20%. Consequently, efficient eradication of AKs is of substantial value in preventing development of NMSCs.^1,2

Topical photodynamic therapy (PDT) has been approved by the FDA since 1999 for the treatment of AKs. PDT involves topical application of a photosensitizer, 20% 5-aminolevulinic acid (5-ALA; DUSA Levulan Kerastick) followed by exposure to blue light 417 nm wavelength. 5-ALA is a precursor of the light activating protoporphyrin IX (PpIX), with PpIX having a maximal absorption at the blue light wavelength of 417 nm in the visible light spectrum. In the presence of molecular oxygen, singlet oxygen is generated and a phototoxic reaction is produced, leading to selective cellular destruction.³

Tumor keratinocytes have a higher 5-ALA absorption rate, particularly for the lipophillic form, relative to normal healthy keratinocytes. This is due to various mechanisms including differences in the activities of the heme biosynthesis enzyme cascade, iron availability, properties of the stratum corneum, and in cell membrane permeability, expressing various transmembrane transporters to actively uptake the molecule.^4-6,7 Higher concentration of porphyrins are produced in rapidly proliferating cells, such as tumor cells, after 5-ALA administration.⁵ Moreover, the microtubule and spindle apparatus which are essential for cellular mitoses are also sensitive to PDT destruction.⁸ With the combination of various cellular mechanism, PDT generates cellular necrosis and apoptosis. On the tissue level, PDT appears to target both the tumor as well as its vascular supply. The benefit of topical ALA- PDT is to selectively target cancerous cells, while preserving the normal surrounding structures.

Slaughter et al,⁹ first introduced the concept of field cancerization in 1953.¹⁰ Since then, the definition has been expanded to include areas which appear clinically normal but have multifocal (pre) neoplastic changes and microsatellite alterations, showing genetic mutations which precede the development of second primary tumors and local recurrences.¹⁰ Field cancerization in skin has been described as a process ‘whereby the whole neighborhood is affected’,^11-14 in this case referring to skin being effect with AKs and NMSCs. Consequently, field cancerization needs to be targeted by field treatment. Many studies have clearly demonstrated ALA- PDT to be a well tolerated procedure that can very effectively eradicate AKs on both clinical and histological levels, through a field therapy approach, while providing good cosmetic outcomes and thus could be very useful for patient with field cancerization.

Recently, several manuscripts have appeared in the literature evaluating the role of chemoprevention with ALA- PDT in helping to clear existing and prevent development of new AKs and consequently reduce the appearance of subsequent NMSCs.^10,15,16 All three of these studies indicate statistically significant reduction in the number of AKs or NMSCs in the fields treated with ALA-PDT over the areas that were not treated. One study, which treated solid organ transplant recipients with ALA-PDT 6 to 9 times per year showed a 95% reduction in the incidence of NMSCs reported,¹⁶ compared with the baseline year prior to ALA-PDT treatment. In addition, the reduction also appears to have varied by sites, with face showing better improvement in the clearance of AKs and longer duration to the appearance of new AKs and NMSCs than scalp and extremities.¹⁵

An interesting question addressed by some of these authors is how long does the clearance from this chemoprevention last, as some of the studies indicate drop off in the clearance at the 6 months follow up with AKs being seen in the fields that were previously clear following the treatment with ALA-PDT. This reappearance of the AK lesions and development of the NMSCs in the treated fields is even more apparent at the 9 months and the 12 months follow ups.¹⁰ As expected, with the development of these AKs, there is also a higher number of NMSCs that have the potential of forming in these areas from these AKs. Perhaps re-treatment with ALA-PDT is indicated three months following the treatment with ALA-PDT in order to maintain clearance of these areas from AKs and preventing subsequent development of NMSCs.