Photodynamic Therapy for Dermatologic Conditions

Indications

The role of PDT in dermatology has expanded considerably over the past 2 decades. Topical PDT has become an established first-line or alternative treatment for actinic keratosis, Bowen disease (also known as squamous cell carcinoma in situ), and superficial basal cell carcinoma. The guidelines, developed under the International Society for Photodynamic Therapy in Dermatology, highlight not only its clinical effectiveness but also its patient-centered benefits, such as minimal invasiveness, reduced pain, and excellent cosmetic results compared to conventional surgical modalities.[2]

Furthermore, PDT continues to gain traction across various healthcare systems worldwide. Beyond oncologic indications, there is growing interest in its application to nononcologic dermatologic conditions, including acne vulgaris, photoaging, viral warts, and localized scleroderma (morphea).[3] These developments reflect an expanding evidence base and increasing clinician confidence in PDT as a versatile and adaptable treatment strategy.

Actinic Keratosis

Actinic keratosis, a premalignant skin lesion, is commonly observed in chronically sun-exposed areas such as the face, scalp, forearms, and the dorsal surfaces of the hands. These lesions frequently occur in clusters, forming areas of field cancerization, where the surrounding skin also harbors subclinical damage. Longitudinal studies estimate that 5% to 20% of actinic keratoses may transform into squamous cell carcinoma, which has the potential to metastasize over 10 to 25 years, with annual conversion rates ranging from 0.25% to 16%.[4][5]Due to the inability to predict which lesions undergo malignant transformation, current clinical guidelines recommend the treatment of all actinic keratoses.[5][6]

For patients presenting with multiple lesions across broad, photodamaged areas, PDT has emerged as a particularly suitable modality. PDT offers the advantage of treating large surface areas in a single session while selectively targeting dysplastic cells. Early treatment is encouraged not only to prevent potential progression to squamous cell carcinoma but also to achieve optimal cosmetic results, especially when lesions are located on cosmetically sensitive sites.

Extensive clinical evidence supports the efficacy of PDT in managing actinic keratoses. Randomized controlled trials evaluating methyl aminolevulinate-based PDT (MAL-PDT) and 5-aminolevulinic acid-based PDT (ALA-PDT) have demonstrated consistent and high lesion clearance rates.[7][8][9][10][11] Phase III studies of MAL-PDT report complete response rates of approximately 90% following 2 treatment sessions.[8][9][10] Data from pooled studies of ALA-PDT show a similar 3-month clearance rate of 91%, with 89% of patients achieving resolution of at least 75% of lesions.[11] Interestingly, a single MAL-PDT session—with a second session 3 months later administered only if residual lesions persisted—has been shown to achieve outcomes comparable to the standard protocol involving 2 sessions spaced 7 days apart.[10]

When compared to other commonly used therapies, PDT demonstrates favorable outcomes. Two phase III trials found that 2 MAL-PDT sessions were more effective than a single freeze-thaw cycle of cryotherapy. In contrast, a single session showed comparable results to double freeze-thaw cryotherapy.[7][9] A small comparative study of ALA-PDT and 5-fluorouracil (5-FU) also indicated equivalent efficacy between the 2 treatments.[12]

Patient tolerability is a critical factor in treatment selection. PDT is generally well tolerated, with transient adverse effects such as pain, erythema, and irritation typically resolving without intervention. A randomized study involving 36 patients found that ALA-PDT was better tolerated than 5-FU.[13] A separate trial with healthy volunteers showed that MAL-PDT induced significantly less pain than ALA-PDT.[14] Pain management protocols, including cooling methods and topical anesthetics, have been shown to effectively improve patient comfort during PDT sessions.[15]

In addition to its therapeutic efficacy, PDT offers cosmetic benefits, which are particularly important for lesions in visible areas. MAL-PDT has consistently been associated with favorable cosmetic outcomes, with over 95% of cases rated as excellent or good in phase III trials.[7][8][9] Similarly, studies of ALA-PDT report cosmetic success rates above 90% (Food and Drug Administration). Comparative analyses indicate that MAL-PDT achieves significantly better cosmetic outcomes than cryotherapy at 3-month follow-up.[7][9]

PDT is a highly effective and well-tolerated treatment option for actinic keratosis. The ability of PDT to treat large areas of field cancerization, combined with excellent cosmetic outcomes and a favorable safety profile, positions PDT as an effective modality in managing actinic keratosis lesions.

Nonmelanoma Skin Cancers

Basal cell carcinoma is the most common nonmelanoma skin cancer, mainly affecting fair-skinned individuals on sun-exposed areas, such as the face and the neck. Bowen disease, also known as squamous cell carcinoma in situ, is another type of nonmelanoma skin cancer confined to the epidermis. If left untreated, it is considered a precursor to invasive squamous cell carcinoma. The most critical risk factor for the development of basal cell carcinoma and squamous cell carcinoma in situ is exposure to UV radiation, followed by lighter skin complexion, male gender, a history of precancerous lesions, such as actinic keratoses, immunosuppression, and exposure to ionizing radiation.[16] Additionally, individuals diagnosed with nonmelanoma skin cancer are more likely to develop subsequent nonmelanoma skin cancers, particularly within the first year of diagnosis.[2]

Given that both basal cell carcinoma and Bowen disease are highly treatable and have a propensity to develop on cosmetically sensitive areas such as the face, PDT offers a key advantage compared to other treatment options due to its efficacy and favorable aesthetic outcomes. When considering PDT for the treatment of basal cell carcinoma or Bowen disease, careful selection of the photosensitizer and the appropriate light wavelength is essential. MAL and 5-ALA are the 2 main photosensitizers used in topical PDT and are metabolized into photoactive porphyrins in the neoplastic tissue.[2] Incubation time depends on the specific topical photosensitizer used, allowing adequate time for production and accumulation of porphyrins for effective PDT. Additionally, the wavelength of the broad-spectrum light chosen is also essential for achieving effective treatment with PDT. Red light has a longer wavelength of light (600-1200 nm) compared to blue light (400 nm), allowing for better treatment of thicker lesions such as basal cell carcinoma and Bowen disease.[2]

There have been multiple clinical trials that focus on the efficacy of PDT in the treatment of basal cell carcinoma. In a phase III clinical trial comparing the safety and efficacy of BF-200 ALA gel with BF-200 MAL cream in the treatment of basal cell carcinoma, 93.4% of the patients in the BF-200 ALA group achieved clearance after 12 weeks compared to  91.8% of the patients in the BF-200 MAL group.[3] This study was pivotal in demonstrating the similar efficacies of ALA and MAL when used in conjunction with PDT in the treatment of basal cell carcinoma. Additionally, the frequency and severity of treatment-emergent adverse events were comparable between the ALA and MAL groups, with patients reporting mild-to-moderate intensity adverse events.[3]

In contrast to basal cell carcinoma, Bowen disease has posed a more difficult challenge to treat with PDT due to the lack of a standardized treatment regimen, leading to different treatment outcomes. Variability in anatomic site, tumor size, number of PDT sessions, and incubation time with ALA has led to inconsistencies in the data, making it unclear whether these factors significantly influence treatment response.[17] However, topical ALA-based PDT generally achieves a clearance rate of 86% to 93% for Bowen disease lesions in 1 to 2 treatment sessions.[3] Data from 3 smaller randomized trials focusing on the treatment of Bowen disease with PDT showed PDT to be equivalent to cryotherapy,[18] superior to topical 5-FU,[19] and more effective when administered with red light compared to green light.[20] Additionally, topical PDT offers a key advantage in the treatment of Bowen disease by effectively treating large or multiple lesions as well as those located in areas prone to poor wound healing.[3] 

Off-Label Indications

In addition to its routine use for treating superficial nonmelanoma skin cancers and actinic keratoses, PDT has also been used to treat a wide range of common dermatologic conditions. For example, treatment-resistant viral warts have shown notable improvement when treated with red-light PDT with 20% 5-ALA.[21] Similarly, red-light PDT with 20% 5-ALA has shown efficacy in treating condylomata acuminata, with the majority of patients achieving complete lesion clearance.[22] Compared to other wart therapies, PDT represents a significant advancement in wart treatment, as it not only targets visible lesions but also can treat latent HPV-infected cells and helps reduce the overall viral load.[23][24]

Additionally, PDT has also been used due to its antimicrobial and anti-inflammatory properties in the treatment of acne vulgaris. Although no standardized PDT protocol exists for the treatment of acne, red-light PDT generally has been shown to inhibit and destroy sebaceous glands.[25]

Contraindications

Contraindications to PDT include a history of porphyria, hypersensitivity to topical photosensitizers, and cutaneous tumors that are unresponsive to treatment.[26]

Technique or Treatment

The fundamental mechanism of PDT involves the administration of a photosensitizing agent, which selectively accumulates in abnormal, rapidly proliferating cells. Upon exposure to light of a specific wavelength, the photosensitizer becomes activated, leading to the production of reactive oxygen species that induce cytotoxicity and cell death. This targeted mechanism allows PDT to effectively treat diseased tissue while sparing surrounding healthy skin. Three main mechanisms have been proposed to explain the effects of PDT—destruction of tumor vasculature, direct eradication of tumor or neoplastic cells, and activation of the immune response.[27] In the literature, no single mechanism is favored over the other, and it is likely that all 3 mechanisms work synergistically to target abnormal cells.

Among the most commonly used photosensitizers in dermatologic applications are 5-ALA and MAL, both of which are precursors to protoporphyrin IX, a potent endogenous photosensitizer. These photosensitizers bind to low-density lipoproteins, which subsequently enables their cellular entry via LDL receptor-mediated endocytosis. Once inside the cell, they are transported to the mitochondria, where they are metabolized into the photoactive protoporphyrin IX.[28] MAL has demonstrated higher selectivity for neoplastic cells compared to ALA, enhancing its utility in the treatment of conditions such as actinic keratosis and superficial basal cell carcinoma.[2] The treatment protocol includes an essential incubation period to allow sufficient conversion of the photosensitizer to protoporphyrin IX within the target tissues. For example, MAL typically requires a 3-hour occluded incubation period, whereas ALA may necessitate 14 to 18 hours for optimal accumulation in the epidermis. Initially, it was hypothesized that the lipophilic profile of MAL compared to the more hydrophilic profile of ALA allows MAL to penetrate deeper into tissue, making it a better option for nodular and infiltrating basal cell carcinoma.[3] However, 2 smaller studies comparing the efficacy of ALA-PDT and MAL-PDT in patients with nodular basal cell carcinomas—regardless of whether the lesions were debulked or left untreated—found no significant difference in response between the 2 photosensitizers.[29]

Following incubation, the affected area is exposed to a light source whose wavelength corresponds to the absorption spectrum of protoporphyrin IX. The choice of light source—commonly blue light (400-450 nm), red light (approximately 630 nm), or daylight—is dictated by the desired depth of tissue penetration. Blue light is suitable for more superficial lesions, such as actinic keratoses, whereas red light is preferred for thicker lesions such as superficial basal cell carcinomas due to its greater tissue penetration depth.[30] The light-activated photosensitizer interacts with molecular oxygen to generate reactive oxygen species, including singlet oxygen and free radicals, which damage cellular components and induce apoptosis, necrosis, or autophagy.

Complications

As with any medical procedure, PDT carries a risk of complications, which can occur acutely or in the long term. Acutely, some complications that can occur within hours to days of PDT include pain at the site treated, erythema, edema, desquamation, and pustule formation. Because photosensitizers can continue to form after PDT, patients are advised to avoid sun exposure for at least 24 to 48 hours post-treatment to minimize erythema and inflammation. Complete sun avoidance and protective clothing are more effective than inorganic sunscreen during this period.[31]  

Other acute, but more rare, complications include urticaria, contact dermatitis, and erosive pustular dermatosis of the scalp.[32] Out of all the potential complications listed, pain is the most common symptom experienced acutely after PDT, with over 50% of patients reporting severe pain.[33] Late-onset complications include pigment changes, scarring, and, more rarely, bullous pemphigoid and carcinogenicity.[32] In the literature, only 2 cases of bullous pemphigoid have been reported; one involving bullae formation directly in the area of Bowen disease treated with PDT, and the other involving bullae formation in unrelated areas.[34][35] There have also been reports suggesting a potential risk of carcinogenicity following PDT, including, but not limited to, cases of basal cell carcinoma, invasive squamous cell carcinoma, and keratoacanthoma.[36][37][38][39]

Clinical Significance

Clinicians often use PDT over other treatment modalities, such as cryotherapy, imiquimod, and surgical excision, for the treatment of actinic keratoses and nonmelanoma skin cancers due to its unique combination of benefits. PDT is a rather noninvasive procedure that allows patients to experience minimal adverse effects and little downtime. Additionally, the ability of PDT to treat multiple lesions simultaneously with minimal carcinogenic risk and mild general toxicity makes it a highly attractive treatment modality.[40] Another key advantage of PDT is its ability to selectively target abnormal epidermis that overlies actinic keratoses and superficial skin tumors. This selectivity arises from the accumulation of porphyrin metabolites, which are produced when topical preparations, such as 5-ALA and MAL, are incubated topically on the skin before exposure to blue or red light.[3] As a result, PDT not only effectively treats skin lesions but also yields superior cosmetic results, avoiding scarring that typically occurs with surgical excision.

Enhancing Healthcare Team Outcomes

Patients with extensive actinic damage and noninvasive nonmelanoma skin cancers, such as basal cell carcinoma and Bowen disease, may be eligible for PDT. Although PDT is considered a highly effective, tissue-sparing treatment, both patient opinion and clinician recommendation should be heeded to determine the best treatment course for the individual patient. A collaborative approach between clinicians and patients is essential to ensure that all risks and benefits of each treatment option are thoroughly discussed. Effective interprofessional communication is also required between primary care physicians, dermatologists, nurses, and other healthcare providers to tailor an individualized treatment plan for patients. Additionally, managing patient expectations regarding cosmetic outcomes and the possibility of having to repeat PDT treatment if the lesions of concern do not resolve are crucial to overall treatment success.

Providing patient-centered care for individuals with nonmelanoma skin cancer requires a collaborative effort among healthcare professionals, including clinicians, advanced practice practitioners, nurses, pharmacists, and other healthcare providers. First and foremost, healthcare providers must possess the necessary clinical skills and expertise when diagnosing, evaluating, and treating this condition. Therapy choice for nonmelanoma skin cancer and actinic keratoses should be distinguished by overall efficacy, patient tolerability, and, most importantly, patient consent. Before initiating treatment with PDT, it is important to disclose any potential adverse effects from the treatment and to thoroughly discuss other treatment options with the patient. Members of the healthcare team have the responsibility to perform their job within their scope of practice to best guarantee a positive therapeutic outcome. After PDT, coordinating care with the healthcare team ensures that the patient is receiving the appropriate post-treatment care, minimizing any safety risks to the patient.