PDT techniques for chemoprevention advance

April 1, 2014

Photodynamic therapy applied every other month shows promise as a chemopreventive regimen, while thermal PDT appears to offer better photosensitizer uptake and long-term results than standard PDT, experts say.

Miami Beach, Fla. - Advances in photodynamic therapy (PDT) involve new application and incubation methods, while data in chemoprevention continue to grow, according to an expert.

Chemoprevention represents an important area of PDT research because, to date, physicians have no approved regimen here, says Neal Bhatia, M.D., a dermatologist in private practice in Long Beach, Calif., and an associate professor of dermatology at the Harbor University of California Los Angeles Medical Center.

“We use both topical and systemic retinoids and other topical agents. But with PDT, you can get a distinct benefit by using it every other month,” Dr. Bhatia says.

In one study, 12 high-risk solid organ transplant recipients underwent PDT every four to eight weeks for two years. Compared to baseline, he says, “Sequential treatment resulted in an almost 95 percent reduction in squamous cell carcinomas at week 24 (Willey A, Mehta S, Lee PK. Dermatol Surg. 2010;36(5):652-658).”

Such a regimen could benefit virtually any high-risk or immunosuppressed patient, such as those with extensive photodamage, diabetes or even those who take biologic drugs, he says. Another study showed that a single PDT session may delay and prevent development of actinic keratoses (AKs) in patients with multiple AKs and a history of nonmelanoma skin cancer (Goldberg LH, Landau JM, Moody MN, et al. J Drugs Dermatol. 2012;11(5):593-597).

Application techniques

As for application techniques, a recent phase 2/3 study has shown that treating the entire photodamaged surface area works significantly better than pinpointing lesions alone (unpublished), as liquid nitrogen cryosurgery does.

“When you just treat the spots,” Dr. Bhatia says, “you lose the benefit of treating the subclinical and developing lesions.”

The same study also showed that three hours’ incubation leads to greater reductions in lesion counts than one or two hours. In patients treated with broad-area application, those who underwent three hours’ incubation achieved median lesion-count reductions of 78.6 and 75 percent at weeks 12 and 24, respectively. Mean lesion-count reductions at the same time points among patients who underwent one and two hours’ incubation ranged between 64.9 and 73.6 percent.

“Incubating for one hour is convenient for some patients,” Dr. Bhatia says. “But in the truest sense of the science, it’s incomplete in terms of converting aminolevulinic acid (ALA) to active protoporphyrin IX.” Most study patients needed two PDT sessions, with the second occurring eight weeks after the first.

 

 

Temperature-modulated PDT

Similarly, he says, temperature-modulated PDT appears to improve results. In a recently completed 20-patient trial, investigators incubated ALA for one hour under occlusion with a heating pad on patients’ extremities (left or right, chosen at random). Then investigators applied 10 J/cm2 of blue light.

At two months post-treatment, clearance rates of study patients’ heated extremities were approximately 88 percent, versus 66 percent on the unheated side (Willey A, Anderson RR, Sakamoto FH. Submitted for publication: Dermatol Surg).

At six months post-treatment, heated limbs generally remained clear, says study co-author Andrea Willey, M.D., assistant clinical professor of dermatology at the University of California, Davis. However, she says, investigators began to observe AK recurrences on unheated limbs at this point. More importantly, she says that some study patients have remained clear up to 1.5 years post-treatment.

“I have also completed a follow-up study of 20 additional patients who were treated on both arms and followed for a year to see if the efficacy lasts. We found that results last for at least a year (manuscript in preparation),” Dr. Willey says.

Just as physicians apply contact cooling during laser or other skin resurfacing procedures, Dr. Bhatia says, “Many dermatologists use a fan to keep the patient’s skin cool during PDT. But the problem is that cooling the skin creates vasoconstriction.” This decreases the amount of oxygen - which must be converted to cytotoxic singlet oxygen to accomplish the desired tissue destruction - present in the treated skin (Tyrrell J, Campbell SM, Curnow A. J Photochem Photobiol B. 2011;103(1):1-7).

Conversely, he says, heating the skin during incubation both increases the absorption of the porphyrin and dilates blood vessels in the heated area.

“The latter creates more of an oxygen layer that can be converted,” Dr. Bhatia says. The result is better uptake of the photosensitizer by tissues, and stronger conversion by the light. These factors appear to result in stronger post-treatment reactions and better long-term results, particularly for subclinical lesions, he adds.

Attitude adjustment

Dermatologists also may need an attitude adjustment regarding PDT, he says. In this regard, Dr. Bhatia recommends focusing on treatment outcomes rather than short-term symptoms. Many dermatologists are so concerned about the pain and redness that patients experience during and after treatment that they overlook the reductions in AK counts patients can achieve about three months post-treatment, he explains.

“If we manage the reactions with good symptomatic control, we can get patients to stick with it, and they will reach those outcomes. But many of us are so concerned about the pain and other issues that we’re reluctant to give patients a second treatment,” or to use PDT at all.

“Another subject of some controversy is the role of antihistamine,” which Dr. Bhatia says physicians can prescribe to minimize the spike in mast cells that occurs over approximately 72 hours after PDT. “That’s still not a proven protocol - it’s theoretical, based on fact that in the first 72 hours, there is a high proliferation of mast cells as a result of the histamine release. Patients experience anticipated swelling, redness and itching (Brooke RC, Sinha A, Sidhu MK, et al. J Invest Dermatol. 2006;126(10):2296-301).”

Giving an antihistamine early on can help reduce some of these reactions without hindering outcomes, he says. Conversely, using steroids might quell the inflammatory reaction to a degree that compromises results, Dr. Bhatia says.

Disclosures: Dr. Bhatia is a consultant and investigator for DUSA Pharmaceuticals. Dr. Willey is an adviser for DUSA and has received honoraria from the company.