Enhancing tolerability in photodynamic therapy for actinic keratosis without compromising efficacy

Abstract

The study by Tanew et al. presents a well-designed investigation into the efficacy of different illumination protocols in photodynamic therapy (PDT) for actinic keratosis (AK).¹ The trial included 56 patients who received 5-aminolevulinic acid (ALA) PDT in four symmetrical areas of the face and scalp.

The primary aim was to assess whether reducing the light dose and/or fluence would affect the efficacy of PDT. No difference was found in treatment efficacy, including recurrence rates and the development of new AKs, when the total light dose and fluence rate were halved compared to the standard protocol (red light: 37 J/cm², 62 mW/cm²). Importantly, lowering the fluence rate (light intensity) resulted in significantly less pain during illumination. In contrast, reducing the total light dose alone did not affect pain perception. Additionally, peak phototoxicity, measured 2 days after PDT, did not vary significantly between protocols.

These findings are highly relevant for improving PDT tolerability without compromising therapeutic outcomes. PDT is an effective treatment of AK and field cancerization. During standard red-light PDT, ALA or methyl aminolevulinate is applied to the affected skin and incubated under a light occlusive dressing for 3 h, leading to the accumulation of the photosensitizer protoporphyrin IX (PpIX) in keratinocytes. Activation of PpIX by red-light results in the formation of reactive oxygen species which cause targeted cellular destruction via apoptosis and necrosis.

Previous studies have demonstrated that the standard red-light dose of 37 J/cm² may exceed what is necessary for activation of the accumulated PpIX.² More than 85% of available PpIX is activated after just 18 J/cm², suggesting that the remaining 19 J/cm² may offer little additional benefit.² These results explain why lowering the light dose to half of the standard dose does not affect efficacy in the study by Tannew et al.¹

Pain during standard red-light PDT remains one of the most significant drawbacks of the treatment and can lead to interruption or even early termination of the illumination.³ The mechanism underlying PDT-induced pain is closely tied to the synthesis and localization of PpIX. During the 3 h incubation with ALA/MAL, PpIX is synthesized in mitochondria and accumulates in the keratinocytes. As intracellular concentrations rise, excess PpIX is excreted into the extracellular space, where it can incorporate into free nerve endings located in the epidermis.³ Therefore, during illumination, PpIX is not only activated in keratinocytes but also in nerve endings, resulting in the intense burning or stinging pain commonly reported during illumination.

Lowering the light intensity (fluence rate) during illumination has been shown to reduce pain, likely due to the slower rate of PpIX activation.⁴ However, reduction in fluence rate while maintaining the same light dose will result in longer illumination times. Interestingly, Tannew et al. find that efficacy is maintained using the lower and less painful fluence rate while maintaining the treatment time using half of the light dose.¹ This protocol may improve tolerability for the patients, as they will experience less pain for a shorter duration of time.

The introduction of daylight PDT has solved many problems concerning PDT induced pain.⁵ During daylight PDT, continuous photoactivation of PpIX during its synthesis in keratinocytes prevents significant intracellular accumulation. As a result, PpIX does not accumulate in epidermal nerve endings and only small amounts are activated in keratinocytes over an extended illumination period of 2 h. This mechanism contributes to a virtually pain-free treatment. However, outdoor daylight PDT is not always possible due to weather dependency and geographical limitation.

Therefore, studies like that of Tannew et al. are crucial in optimizing standard red-light PDT protocols to maintain clinical outcomes while improving the patient experience.

HCW has received speaking honoraria from Galderma, and SRW has received speaking honoraria from Galderma and Galenica.