A Practical Approach: Field Treatment of AKs with PDT

Brian Berman, MD, PhD is Voluntary Professor of Dermatology at The University of Miami Miller School of Medicine and on staff at Skin and Cancer Associates in Aventura, FL. He also serves as a member of the Board of Directors of the American Academy of Dermatology.

Neal Bhatia, MD is Director of Clinical Dermatology and Principal Investigator at Therapeutics Clinical Research in San Diego, CA. Dr. Bhatia has served as Principal Investigator for numerous clinical studies. He is currently an Associate Professor of Dermatology at Harbor UCLA Medical Center, and is widely published and active in professional societies.

Joel L. Cohen, MD is Director of AboutSkin Dermatology and DermSurgery, PC with offices in Greenwood Village and Lone Tree, CO. He is a board-certified dermatologist and has completed a Dermatologic Surgery and Aesthetic fellowship in Mohs micrographic surgery, cutaneous oncology, facial reconstruction, cosmetic surgery, and laser surgery. He is Associate clinical professor at University of California at Irvine.

Michael Gold, MD is founder of Gold Skin Care Center and Tennessee Clinical Research Center located in Nashville, TN. Dr. Gold is also a Clinical Assistant Professor at Vanderbilt University School of Nursing and an Adjunct Assistant Professor at Meharry Medical College School of Medicine in Nashville.

Gary Goldenberg, MD is a medical and cosmetic dermatologist in practice at Goldenberg Dermatology in New York City. He is an Assistant Clinical Professor of Dermatology at The Icahn School of Medicine at Mount Sinai Hospital in New York City. He is board certified in both dermatology and dermatopathology.

Andrea Willey, MD is a leader in dermatologic surgery and aesthetic technologies and runs Andrea Willey MD Surgical & Aesthetic Dermatology, her practice in Sacramento, CA. She is a Mohs and reconstructive surgeon who is passionate about her craft and has cured thousands of patients of skin cancer. She is also a pioneer in the advancement of thermal photodynamic therapy.

Actinic keratoses (AKs) are among the more common lesions that dermatologists treat. Although considered pre-cancerous, data show a link between AKs and squamous cell carcinoma (SCC) and field cancerization, making early diagnosis and treatment important.^1,2

“We commonly refer to actinic keratoses with our patients as pre-cancers—some people refer to them as keratinocyte intraepidermal neoplasia, or an evolving, or on the spectrum of an evolving, skin cancer,” says Joel L. Cohen, MD. “But we don’t know which of these red, rough, and scaly lesions are going to go on to the next step to progress to a skin cancer. There are studies out there showing varying rates of that. But nevertheless, we do treat these AKs because we simply don’t know.”

Gary Goldenberg, MD, says it is imperative that these lesions are treated, citing scientific evidence showing how normal non-sun exposed skin can progress to squamous cell carcinoma in a linear progression of multiple mutations in the keratinocytes from normal to actinic keratosis to in situ carcinoma to invasive carcinoma.¹

Dr. Goldenberg describes a 2009 Veterans Affairs study that looked at the role AKs may play in the overall burden of keratinocyte carcinomas (KC). In total, 7, 784 AKs were identified on the face and ears of 169 participants. The risk of progression of AK to primary SCC (invasive or in situ) was 0.60 percent at one year and 2.57 percent at four years. Approximately 65 percent of all primary SCCs and 36 percent of all primary BCCs diagnosed in the study cohort arose in lesions that previously were diagnosed clinically as AKs. The majority of AKs (55 percent) that were followed clinically were not present at the one-year follow-up, and the majority (70 percent) were not present at the five-year follow-up. In this study, the authors concluded that the results suggested that AKs may play a greater role in the overall burden of keratinocyte carcinomas than previously documented.³

It is known that anywhere between 0.025 and 16 percent of AKs can progress to invasive SCC—extrapolation studies suggest the risk of progression is approximately eight percent, with risk varying with age, gender, chronic UV exposure, and location of AKs,^4,5 says Neal Bhatia, MD. And one retrospective review study of biopsy-proven AKs at eventual site of SCC showed that the time range for conversion from AK to SCC is two to 65 months, with a mean range of 24.6 months.⁴

The spontaneous regression rate of AKs is estimated to be 15-25 percent in a one-year period, compared to the occurrence rate of invasive SCC, which is five to 20 percent over follow-up periods of 10 to 25 years with a 0.1 percent and 0.24 percent transformation rate from AK to SCC in one year. And, Dr. Bhatia adds, 82.4 to 100 percent of patients with invasive SCC arising on sun-exposed areas have a history of AK.^6,7,8

Based on this data and what we know anecdotally, Dr. Bhatia says, it’s possible to reduce the risk of skin cancer by treating what we see as well as what is on the way.

The Case for Field Treatment

The issue with actinic keratoses, explains Brian Berman, MD, is that if you see a few, there’s a very high likelihood that the surrounding area that has no visible AKs already has changes that are consistent with actinic keratoses, or what are considered sub-clinical AKs.

Michael Gold, MD agrees. “As dermatologists we always recommend treating AKs and treating them early because we know that there is a malignant potential for all of these lesions to become squamous cell carcinomas. The earlier the treatment, the best chance to avoid a diagnosis of malignancy,” he says. “We can treat individual lesions, which is what we do when we use liquid nitrogen or curettage an AK lesion, but we know when we do this we are missing pre-clinical AKs—those that are forming or just under the skin surface. We are also not taking into account that all of these lesions occur on actinically damaged skin, so the potential for new AKs to develop in these areas is also increased as compared to those who have not had the same sun exposure. So that is where the field concept developed—treating the visible and the pre-clinical AKs at the same time.”

The standard of care and most commonly used treatment for actinic keratoses in the US is still cryotherapy with liquid nitrogen—it has been around forever, it is simple to do, and reimbursement is decent for this procedure, Dr. Gold says. Some physicians will use curettage if there is suspicion of malignancy. If a patient has an isolated lesion, liquid nitrogen can be very effective, Dr. Cohen says, but he adds that it’s important to educate patients about AKs to help them understand that our goal is to decrease the number of subclinical lesions they have and that although they may not be able to see them, it’s clear that the they have sun damaged skin and other visible features of subclinical AKs. He explains that field therapy vs. a destructive modality can help to clean up the overall photodamage and treat both the visible and invisible lesions.

This concept of subclinical lesions does need to be explained to patients, Dr. Gold adds. Most patients don’t understand that they may only have four to 10 lesions on their face, but that there may be 20 underneath the skin, especially if they are presenting with AKs for the first time.

“My job is to prevent patients from needing to see a surgeon,” Dr. Goldenberg explains, comparing field therapy to preventative medicine. When you treat the entire field, you’re also helping to prevent new lesions from developing as well as helping prevent the development of AK to a skin cancer that needs to be surgically removed.

There are several effective topical field therapy options, including 5-fluorouracil (5-FU) (Carac, Efudex, Fluoroplex, Tolak), chemical peels, diclofenac sodium (Solaraze), imiquimod (Aldara, Zyclara), and ingenol mebutate (Picato). They have all been shown to reduce the number of AKs from baseline, give or take, by about 80 percent, says Dr. Berman, but the main issues with the use of topicals are the local skin reactions from these various products and the number of applications that are required to exert their efficacy. Agreeing that these topical therapies are efficacious and beneficial in the field management of AKs, Dr. Goldenberg notes that patients should be counseled and made aware of potential issues associated with these topical therapies, including redness, scaling, and crusting, and resulting downtime.

“So it’s a mixture of tolerability and whether patients are going to be compliant with use in order to achieve the efficacy that’s in the literature. The number of applications of the various creams and gels range from as few as two days total, two applications, in the case of ingenol mebutate 0.05%, all the way up to 180 applications according to the FDA indication for Diclofenac 3%,” Dr. Berman says. “And the problem is that patients are often not compliant with any medication and likely would not apply any medication 180 times religiously. Even if the efficacy is there, if it requires 180 applications, patients will not achieve that efficacy.”

In terms of compliance and user-friendliness, Dr. Berman suggests ingenol mebutate with its two- or three-day dosing pattern would be best. But it is associated with some risk of local skin reactions, so may not be suitable for some patients. With 5-FU, patients will need seven to 28 applications—there are four different FDA-approved variations. And imiquimod, which Dr. Berman says is a highly effective immune response modifier, still requires twice-weekly application for up to 16 weeks or about 32 applications with the classic 5% imiquimod or 28 for the 3.75% formulation. The 3.75% cream is available in a metered-dose pump—one to two pumps are applied once nightly for two weeks of treatment, followed by two weeks of no treatment (rest period), and then followed by another two weeks of treatment, which does offer a shorter total treatment duration, increased tolerability, and the ability to treat a larger area, adds Dr. Goldenberg.

“But what it really comes down to, in addition to the compliance and the user friendliness and the degree of local skin reactions, is whether or not the insurance company of the patient will actually pay for these products. There’s a lot of science behind these treatments,” Dr. Berman says. “But if you can’t get it, it doesn’t matter how effective the treatments are.”

It’s about accessibility and tolerability when choosing which topical cream to prescribe for AKs. If a patient has difficulty getting the topical creams or if the patient has a very large number of AKs on the scalp and face, photodynamic therapy field treatment may be the right choice. Dr. Cohen says at his practice, they offer patients a choice regarding field therapy—asking if patients prefer to use a cream at home or want to come into the office to do something, and not have to have the homework. Some people have used topical therapies in the past, like 5FU or imiquimod or ingenol mebutate, and they know that it can result in crusty and irritated skin that can look unsightly for a while.

“For patients who have used 5-FU before, some are willing to deal with those kinds of side effects for up to several weeks, but some patients say, ‘I will never do anything like that again.’ They think about doing ingenol mebutate for a few days. Or, we may think about treating with a shortened therapy, or with imiquimod for two weeks on, two weeks off, two weeks on,” Dr. Cohen says. “But some people are really clear. They would rather come into the office, have us do a PDT treatment, and then they’ll stay indoors and away from any outdoor light for the next couple of days. And that’s very clear cut.”

With an in-office treatment you know your patients are getting the treatment and appropriately so, adds Dr. Berman.

“I’m a skin cancer surgeon, so most of the patients I treat have had skin cancer,” says Andrea Willey, MD. “They often have significant sun damage and a history of skin cancer, so a field therapy is indicated. Because of its efficacy and the ability to complete the treatment in a few hours, PDT is often the preferred treatment for patients with field cancerization.”

Photodynamic Therapy

“We know from years of study that PDT, using ALA and a blue or red light, and methyl ALA, using a red light, can make dramatic changes in one’s skin, as the photosensitizers are absorbed by AKs and by actinically damaged skin—clearing both conditions nicely” Dr. Gold explains. “In fact, PDT has been shown to have a very acceptable cosmetic effect, not always seen with any other modality. PDT fits in nicely when we can document numerous AKs to be treated, when other modalities have failed to control the AKs, and when patients are tired of having liquid nitrogen applied to their skin or tired of being cut.”

PDT came to the US in the late 1990s, notes Dr. Gold, and in 2000, 20% aminolevulinic acid (ALA) solution (Levulan Kerastick) was FDA approved to treat non-hyperkeratotic AKs of the face and scalp with a blue light source (Blu-U). The original FDA indication was for the individual treatment of these AKs. Clinical studies since then have shown full-face and scalp treatment, as well as treatment of the extremities in a full-field manner, have resulted in an effective treatment option for these lesions,^9,10 says Dr. Gold.

Dr. Bhatia also notes that dermatologists have learned that the original (and on label) drug incubation time, which was 14-18 hours with 20% ALA, is not needed in most cases. Clinical studies have shown that short-contact ALA drug incubation—from one to three hours—works with the same efficacy as the longer drug incubation time periods.¹¹

A second ALA was FDA approved in 2016. Aminolevulinic acid hydrochloride (BF-200 ALA, Ameluz) was FDA approved for PDT using the BF-RhodoLED lamp, a narrowband, red light illumination source, for lesion-directed and field-directed treatment of AKs of mild to moderate severity on the face and scalp. This approval was based on results from 779 patients with four to eight mild to moderate AK lesions. The results obtained from these studies demonstrated that BF-200 ALA was significantly superior to the standard of care, with a complete patient response rate of 91 percent when paired with BF-RhodoLED PDT lamp.¹²

In addition, Ameluz showed positive long-term effects with low recurrence over the course of 12 months.¹³ And in a pivotal Phase 3 trial performed on entire treatment fields, BF-200 ALA demonstrated long-lasting skin rejuvenation effects in sun-damaged, but asymptomatic, skin regions.¹⁴

Ameluz differs from Levulan in that it’s a gel formulation rather than a liquid, Dr. Berman says. “It’s a different concentration, it’s 10% rather than 20%, and it’s in a nano formulation, which is better for penetration,” he says.

Dr. Bhatia explains that the nanoemulsion delivery of Ameluz optimizes the transport of the ALA through the stratum corneum and allows penetration of ALA without permeation into the dermis.¹²

“We use a lot of Ameluz in our office,” Dr. Cohen says. “In terms of the way that it’s actually formulated, it’s easy to apply and see the area you’ve covered. The patients have done well with it.”

Dr. Willey says both FDA-approved ALA formulations have been shown to be effective for the treatment of AKs, but the newer ALA 10% gel is a litter easier and faster to apply.

Ameluz is indicated for use with a red light, which does penetrate deeper than blue light, however Dr. Gold says he has found that the ALA is effective with either light source for treating AKs and that clinical studies have shown results are virtually the same with either light source. (See sidebar “Red or Blue”)

Dr. Willey uses both red and blue light in her office, and notes significant aesthetic benefits following treatment with red light PDT compared to other field therapies for AKs.

PDT Treatment Protocol

All physicians have a unique treatment approach based on their years of experience treating AKs. There are general treatment guidelines, says Dr. Bhatia.

• Patients should wash the area to be treated with soap and water and then use an alcohol-soaked 4x4 gauze pad to remove any remaining debris and oil.
• The photosensitizer is then evenly applied to the entire treatment area and a second coat may be applied after the first has dried completely.
• Then, the photosensitizer needs to incubate for 30 minutes to four hours, followed by activation of the photosensitizer by the appropriate light source.
• After treatments, patients should wash the treated area again with soap and water to remove any residual photosensitizer.
• Patients should be instructed to avoid direct sunlight for 48 hours.
• Treatment may be repeated, as needed, for two to three weeks.

“There is no question that prepping the skin with something prior to PDT is beneficial to the skin. Some use microdermabrasion, some use topicals in advance, and most use an acetone scrub before the procedure to enhance the penetration of the ALA,” Dr. Gold says. “Post-treatment, there is no set ‘this or that’—and that is the joy of PDT itself—everything can be customized to the patient based on their needs, their lifestyle, and how much they can tolerate and do in between clinic visits.”

Some patients do experience stinging or burning during the procedure, but Dr. Cohen cautions that it’s important to have patients maintain the recommended distance from the light source to get the most effective treatment. Fans may be used to help increase comfort. However, there is some indication that fans should not be used specifically while incubating, because that may actually decrease the overall conversion of porphyrin.

In order to make the treatment more comfortable for his patients who do report burning or discomfort, Dr. Cohen has his team spray hypochlorous acid (Levicyn) immediately following the PDT treatment on patients who report burning or discomfort.

Patients should be advised that they may experience some redness after treatment, but it typically resolves quickly.

Dr. Willey uses a unique, off-label approach that she says has been very successful in increasing efficacy and reducing variability in response to treatment—thermal PDT. To start, she also has patients wash the treatment area using a mildly exfoliating cleanser prior to gently swabbing with alcohol. She says it important to remove all oil from the skin to ensure penetration of the ALA. Next, ALA gel is applied to the treatment area followed by a heating mask to gently warm the skin during incubation. The patients are treated while they are laying down so it feels more like a spa treatment. After the incubation period, the red light is rolled over to the patient for illumination. Patients are given an ice water mister to apply if they have discomfort during light exposure. Patients wash their face after treatment and then moisturize.

“When you use heat, it’s a very predictable reaction,” Dr. Willey explains. In fact, in a study she led on thermal PDT, she found warming the skin after application of ALA is well tolerated, does not increase side effects, and maintained the long-term efficacy of PDT for the treatment of AKs. Mild skin warming may both improve efficacy and reduce variability of response to PDT in practice.^15,16

Dr. Willey typically calls patients the day after treatment and if they have any discomfort, she recommends ice, Aquaphor™, and Tylenol. Patients follow up in one week, then one month to determine if they need follow-up treatment.

The Promise of PDT

PDT offers patients an excellent option for treating and managing AKs, the physicians agree, and with ongoing research regarding best treatment protocols, the potential use of PDT with red light for treating skin cancers, and improved insurance reimbursement (see sidebar “Crack the Code”), there is a lot to be excited about now and for the future of treating AKs.

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10. Gold MH, Nestor MS. Current treatments of actinic keratosis. J Drugs Dermatol. 2006 Feb;5(2 Suppl):17-25.

11. Pariser DM, Houlihan A, Ferdon MB, Berg JE. PDT-AK investigational group randomized vehicle-controlled study of short drug incubation aminolevulinic acid photodynamic therapy for actinic keratoses of the face or scalp. Dermatol. Surg. 2016, 42, 296–304.

12. Maisch T, Santarelli F, Schreml S, Babilas P, Szeimies RF. Fluorescence induction of protoporphyrin IX by a new 5‐aminolevulinic acid nanoemulsion used for photodynamic therapy in a full‐thickness ex vivo skin model. Experimental Dermatology 2010; 19: e302–e305.

13. Dirschka T, Radny P, Dominicus R, Mensing H, Brüning H, Jenne L, Karl L, et al. Long-term (6 and 12 months) follow-up of two prospective, randomized, controlled phase III trials of photodynamic therapy with BF-200 ALA and methyl aminolaevulinate for the treatment of actinic keratosis. Br J Dermatol. 2013 Apr;168(4):825-36.

14. Reinhold U, Dirschka T, Ostendorf R, et al. A randomized, double-blind, phase III, multicentre study to evaluate the safety and efficacy of BF-200 ALA (Ameluz(®) ) vs. placebo in the field-directed treatment of mild-to-moderate actinic keratosis with photodynamic therapy (PDT) when using the BF-RhodoLED lamp. Br J Dermatol. 2016;175:696-705.

15. Willey A, Anderson RR, Sakamoto FH. Temperature-modulated photodynamic therapy for the treatment of actinic keratosis on the extremities: a pilot study. Dermatol Surg. 2014 Oct;40(10):1094-102.

16. Willey A1, Anderson RR, Sakamoto FH. Temperature-Modulated Photodynamic Therapy for the Treatment of Actinic Keratosis on the Extremities: A One-Year Follow-up Study. Dermatol Surg. 2015 Nov;41(11):1290-5.