Shedding Light on Precancers

Actinic keratoses (AKs; also known as solar keratoses) are the most common precancer that forms on the skin. These lesions are caused by chronic UV exposure from sunlight and/or indoor tanning. With this being a common skin condition seen in the dermatology office, we will discuss a form of treatment known as photodynamic therapy (PDT).

Background on PDT

PDT was discovered by accident in the late 1800s by Oscar Raab, a medical student who was studying infusaria and their interaction with fluorescent dye. He found that intense light applied to the dye resulted in the destruction of the infusaria organisms.¹ Although many patients were being treated in the early 1900s for malignancies of the skin, PDT lost favorability. However, Lipson and Schwartz expanded research on PDT in the 1950s and 1960s. Their studies demonstrated that photosensitizing agents fluoresce and demarcate tumors in addition to ablating tumors. In the next decade, Dr Thomas Dougherty, known as the “Father of PDT,” developed various aspects of PDT that are still used in today’s practice, including a photosensitizing drug and a reliable light source. He also conducted clinical trials to prove the value of PDT to the medical oncology community.¹

Photosensitizers are structures naturally or synthetically created that transfer light energy and create a photodynamic reaction.¹ This occurs when the photosensitizing agent is absorbed preferentially into cells that have an increased mitotic rate. When the photosensitizer is exposed to a certain light wavelength, it transfers to its excited singlet state. In this singlet state, the photosensitizer can then decay back to its original state or cross into the longer duration of a triplet state, which allows the photosensitizer to interact with other molecules in two different reactions. In type 1 reactions, free radicals are produced by either the removal of a hydrogen atom or the transfer of an electron between the substrate and photosensitizer. A type 2 reaction has the photosensitizer react with oxygen to produce reactive oxygen species, which are harmful to surrounding cells and responsible for the desired destructive events of PDT² (Figure).³ Notably, PDT induces cell death through apoptosis, cellular necrosis, and autophagy in the cells with increased mitotic rates.²

Aminolevulinic acid (ALA), a potent photosensitizer that is a biological precursor to protoporphyrin IX, and methyl-aminolevulinic acid (MAL), the methylated ester form of ALA, are commonly utilized in dermatologic applications of PDT.² In humans, 5-ALA goes through a series of conversions within the cytosol and is then converted within the mitochondria to protoporphyrin IX. This is then chelated with iron with the enzyme ferrochelatase to produce heme.⁴ Cancer cells lack the enzyme ferrochelatase, allowing the accumulation of protoporphyrin IX, which leads to cell death via apoptosis or necrosis. The United States has two FDA-approved medications of ALA^5,6; the older ALA is a solution, whereas the newer ALA, approved in 2016,⁶ is a micronized gel formulation. This micronized form is a nanoemulsion that is thought to aid in the delivery of the ALA directly to the epidermal layers presumably by fusion of the vesicles with the lipids in the stratum corneum.

Each photosensitizer has a specific wavelength of light and intensity of light fluency required for activation.² Both blue and red light are utilized for the treatment of precancers as well as superficial nonmelanoma skin cancers. Blue light is traditionally utilized for the treatment of AKs, as it has a wavelength of 450 to 490 nm, which is a relatively short high-energy wavelength. Although less energetic, red light has a wavelength of 630 to 700 nm, which allows for deeper penetration⁷ and has a better chance of destroying deeper tumors such as squamous cell carcinoma (SCC) in situ and superficial basal cell carcinoma (BCCs).

The Soret band, in which maximum absorption ranges from 360 to 400 nm, differs from the Q bands, or the four smaller peaks between 500 and 635 nm.⁸ The Soret band has the highest maximal absorption but the lowest degree of penetration. At around 630 nm, the light can penetrate the first 5 mm of most tissue.⁹ Thus, the utilization of both red and blue light concomitantly allows for improved treatment of field disease by targeting both superficial and deeper tissues.

Treatment of AKs with PDT has a 3-month clearance rate of 89% to 92%, according to the European guidelines published in 2013.¹⁰ The advantage of utilizing PDT in lieu of topical agents alone, such as 5-fluorouracil (5-FU) cream or imiquimod, is that it is an in-office procedure that is generally well tolerated and has a quicker recovery period.¹¹ Another benefit of PDT is that a larger surface area can be more easily treated, allowing for treatment of subclinical lesions adjacent to clinically apparent lesions.²

PDT in Practice

Although topical 5-FU is considered a standard treatment of AKs when used as prescribed, our practice’s experience has found that the compliance to the prescribed regimen (twice daily for 2 weeks on the face; 3 weeks on scalp and extremities) is less optimal. Therefore, in our experience, we have seen better results with patients applying 5-FU to focal areas and in-office PDT for broader surface areas.

In-office PDT procedure starts with the patient being wiped down with isopropyl alcohol and acetone to remove oils from the skin. Then the ALA solution or micronized ALA gel is applied to the entire treatment area. The patient is then allowed to incubate for a specified amount of time before undergoing the light treatment. Patients with a mild to moderate amount of sun damage generally have a 1- to 2-hour incubation period, allowing for the buildup of protoporphyrins. However, patients who have either refractory AKs after undergoing the light or have severe sun damage may benefit from a longer incubation time of 3 to 4 hours.

In our office, we use a blue light illuminator with a time control of 16 minutes, 40 seconds (FDA-approved time = 1000 seconds) or a red/blue light light-emitting diode for 15 minutes. Variables that determine PDT reaction and results include incubation time, amount of photosensitizer utilized, whether curettage or ablative laser was utilized prior for hypertrophic AK, and patient history of sun damage. In our practice, we tend to use sharp curettage on thicker, scaly lesions to allow the solution to penetrate easier, allowing a better chance for the lesion to be destroyed. If patients have numerous hypertrophic AKs, we employ an ablative fractioned carbon dioxide (CO₂) laser to remove thicker plaques and create microchannels, allowing the solution to penetrate deeper. This does cause more discomfort for the patient undergoing the light, but we have found this produces a better outcome of eliminating sun damage and may have clinical improvement in cosmesis.  A study showed ablative fractionated CO₂ with PDT had a 100% cure rate of grade I AKs at 3 months follow up compared with 80% with PDT alone.¹²

Side effects of PDT include erythema, photosensitivity, pain, edema, postinflammatory pigmentary alteration, exfoliation, itching and risk of secondary infection. Screening for contraindications should be performed before the patient undergoes PDT and should include history of systemic lupus erythematosus, porphyria, a nonresponsive tumor, photosensitive dermatoses, or allergy to the photosensitizer.¹³ It is important to note the need for antiviral prophylaxis (acyclovir 400 mg twice daily for 5 days) if the patient has had a history of herpes simplex virus infection, because the light source can illicit an outbreak. Our office also screens for a history of methicillin-resistant Staphylococcus aureus or nasal sores and will prescribe prophylactic doxycycline (100 mg twice daily for 5 days) to take immediately after the procedure to prevent complications.

PDT aftercare includes a immediate application of aloe with lidocaine gel to alleviate any discomfort. We prescribe triamcinolone 0.1% cream that the patient begins using on postoperative day 1, and we encourage the use of moisturizers such as mineral oil-hydrophil petrolat or petroleum jelly, although nonscented moisturizing creams or lotions can also be used. We ask the patient to remain indoors and away from windows and screens since sun exposure can cause an exacerbation and intensify the reaction for 48 hours after the procedure.

Conclusion

Overall, PDT is an effective and safe first-line treatment for AKs and second-line treatment for superficial BCC and SCC in situ. Additionally, there is anecdotal and smaller case studies evaluating the utility of PDT in other conditions, such as acne vulgaris, lichen sclerosus et atrophicus, cutaneous T-cell lymphoma, rosacea, molluscum contagiosum, human papillomavirus infections, scar treatment, and photoaging.¹³ However, further research and clinical trials are still needed to evaluate its effectiveness.

In our practice, PDT serves a key role in our management of patients with severe actinic damage and too numerous to count AKs. Based on the patient’s degree of sun damage, thickness of AKs, and tolerability, the provider can select a PDT regimen with the appropriately adjusted variables, such as incubation time, prior curettage or fractionated CO₂ laser, and the combination of blue and red light sources, to yield an excellent clinical result and potentially avoid or minimize the patient’s need for surgery in the future.

Disclosure: Mr Hasbargen is an advisor for Sun Pharma.

Mr Hasbargen is a physician assistant practicing with Dermatology Associates of Tallahassee, FL. He is also the publication and education chair of Diversity in Dermatology and is a diplomate fellow of the Society of Dermatology Physician Assistants and is on faculty at Florida State University PA program.

References

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5. Levulan kerastick (aminolevulinic acid HCI) topical solution. Drug approval package. U.S. Food & Drug Administration. April 10, 2002. Accessed September 28, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/20-965_Levulan.cfm

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