Nonmelanoma skin cancers (NMSCs), primarily basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), are prevalent malignancies. Actinic keratoses (AKs), precancerous lesions, significantly increase the risk of cSCC development. Major risk factors include age, skin phototype, and chronic ultraviolet (UV) radiation exposure. Field cancerization, characterized by subclinical genetic alterations in seemingly normal skin, further complicates treatment. Photodynamic therapy (PDT) offers a non-surgical treatment option involving topical photosensitizers (ALA, MAL, BF-200 ALA) activated by visible light. These photosensitizers produce reactive oxygen species, inducing apoptosis and necrosis of atypical keratinocytes. While ALA-PDT is approved in the USA for AKs, its use for BCC and cSCC is off-label. This review focuses on current and ongoing research to improve PDT outcomes, tolerability, and cosmesis in patients with AKs, BCCs, cSCCs, and field cancerization.

The authors conducted a literature review using PubMed, searching for articles from inception to February 2022 using keywords related to aminolevulinic acid, photodynamic therapy, specific cancers, and aspects of efficacy and tolerability. The review synthesizes existing studies, focusing on advances in clinical application, novel PDT protocols, and treatment in organ transplant recipients. Several key studies are referenced throughout the review, comparing various PDT techniques and treatment modalities, including different photosensitizers, light sources, and pre-treatment methods. The review also discusses studies examining pain management strategies and the use of PDT in treating field cancerization.

This is a narrative review, meaning it synthesizes existing research rather than presenting original data. The authors searched PubMed for relevant articles published up to February 2022 using specific keywords related to photodynamic therapy, aminolevulinic acid, different types of skin cancers, and aspects such as efficacy and pain management. The search terms included combinations of aminolevulinic acid or aminolevulinate with photodynamic therapy, along with terms like field-directed treatment, squamous cell carcinoma, basal cell carcinoma, efficacy, pain, and tolerability. The authors selected and summarized the most relevant findings from identified studies, incorporating additional recent publications to present a comprehensive overview of the topic. The review does not include any new studies with human participants or animals.

The review highlights several key findings regarding PDT for AKs, BCCs, and field cancerization: * **Efficacy for AKs:** BF-200 ALA-PDT demonstrated superior efficacy compared to other treatments in a meta-analysis of European studies. * **Field Cancerization Treatment:** Clinical trials showed ALA-PDT to be safe and effective for field cancerization, reducing the number of AKs and new NMSCs. * **BCC Management:** PDT, often combined with curettage for thicker lesions, showed promising results for superficial and nodular BCCs, with high clearance rates reported in multiple studies. * **Alternative Light Sources:** Intense pulsed light (IPL) and pulsed-dye lasers (PDL) showed potential as alternatives to conventional light sources, potentially reducing pain. * **Improving Efficacy:** Microneedle pretreatment and thermal conditioning during incubation showed mixed results in enhancing photosensitizer absorption, while ablative fractional resurfacing (AFR) showed promising results. * **Improving Tolerability:** Shortening incubation time and utilizing daylight PDT (DL-PDT) significantly reduced pain without compromising efficacy. * **Organ Transplant Recipients:** PDT, especially with modifications like DL-PDT or AFR-assisted PDT, is a valuable option in this high-risk population.

The review effectively addresses the research question by summarizing existing evidence on advancements in PDT for AKs and NMSCs. The significance of the findings lies in the identification of various strategies to enhance PDT's efficacy and tolerability. The discussion highlights the importance of minimizing pain and optimizing treatment protocols for improved patient adherence, particularly in treating field cancerization, which requires repeated treatments. The findings have significant relevance to dermatology, offering clinicians valuable insights into improving PDT outcomes and expanding its applications. The need for larger, more diverse clinical trials to further validate the findings and address limitations is emphasized.

PDT is a valuable non-surgical treatment option for AKs, BCCs, cSCCs, and field cancerization. High clearance rates have been demonstrated in numerous studies. Innovations in light sources, photosensitizer application, and pretreatment methods offer potential improvements in efficacy and patient experience. Further research is crucial to optimize protocols, enhance long-term adherence, and expand PDT's use across diverse populations and cancer types.

As a narrative review, this study is limited by its reliance on existing literature. The selection of studies might have introduced bias, although the authors attempted to include relevant and high-quality studies. The lack of original data and the absence of a systematic meta-analysis of all the cited studies limits the strength of the overall conclusions. Furthermore, the heterogeneity of study designs and populations across included studies makes direct comparisons difficult and limits the strength of some conclusions.