Topical and oral chemical pretreatments for photodynamic therapy in actinic keratoses: A scoping review.

BACKGROUND

Photodynamic therapy (PDT) is an established field-directed treatment for actinic keratoses (AKs). PDT efficacy is reduced in thicker, treatment-resistant lesions. Pharmacologic pretreatment has been explored as a strategy to improve photosensitizer penetration, protoporphyrin IX (PpIX) accumulation, and lesion clearance.

OBJECTIVE

To systematically review the evidence on topical and oral chemical pretreatments used before PDT for AKs.

METHODS

PubMed, Embase, and Scopus were searched for English-language human studies evaluating pharmacologic pretreatment before PDT for AKs. Interventional studies reporting clearance, recurrence, fluorescence, or adverse outcomes were included.

RESULTS

Nineteen studies published from 2009 to 2025 met the inclusion criteria. Pretreatments included oral vitamin D (VD), and topical VD-analogs, 5-fluorouracil (5-FU), retinoids, urea, salicylic acid, corticosteroids, diclofenac, and ingenol mebutate. The most consistent improvements in PDT response were observed with oral VD, and topical VD-analog or 5-FU pretreatments, particularly in grade II and thicker lesions. Several studies also demonstrated increased PpIX fluorescence after pretreatments. Retinoids showed mixed results. Urea and salicylic acid generally increased efficacy to a level comparable to curettage. Corticosteroid pretreatment did not appear to improve efficacy, whereas diclofenac showed limited short-term benefit but possible longer-term reduction in lesion burden. Ingenol mebutate pretreatment only showed a statistically nonsignificant reduction in AKs.

CONCLUSIONS

Pharmacologic pretreatments can enhance PDT response, especially in thicker, more resistant AKs. Currently, oral VD and topical VD analogs, as well as 5-FU, have the strongest supporting evidence. The heterogeneity in study design, pretreatment regimens, and outcome measures limits direct comparison.