Warming the skin during PDT incubation period boosts porphyrin synthesis

Miami Beach, Fla. - For photodynamic therapy (PDT), an expert says, heating the skin during incubation increases porphyrin synthesis, improving results and potentially cutting incubation times.

“Porphyrin synthesis is profoundly temperature sensitive,” says Andrea Willey, M.D., assistant clinical professor of dermatology, University of California, Davis. Additionally, “Skin temperature varies parabolically with room temperature, and this relationship is highly clinically relevant.” The average room temperature, she notes, ranges between 18 degrees and 26 degrees Celsius.

Furthermore, a small study shows that with the photosensitizer aminolevulinic acid (ALA), increasing the temperature of healthy skin by 10 degrees Celsius approximately triples porphyrin production (Sakamoto FH. Unpublished). “This shouldn’t be a surprise, because all enzymatic processes are temperature-dependent. Conversely, when you cool the skin with a contact cooling device, no porphyrins are made.”

Such factors are important because normal skin temperature generally ranges between 30 degrees and 34 degrees Celsius, she says. “It depends on the ambient conditions and location on the body.” In the latter area, Dr. Willey explains, the extremities are generally at the cooler end of the spectrum, the face at the warmer end. “The purpose is to keep the brain warm, through vasoconstriction and dilation that are tightly regulated by temperature sensors located primarily in the skin,” she says.

Enhanced results

Because lower ambient temperatures inhibit porphyrin production, Dr. Willey says, achieving warmer temperatures for PDT on extremities appears to be a promising way to improve results. Normally, “Efficacy is tremendously reduced when we do PDT on extremities because the skin temperatures are naturally lower. Yet due to the drawbacks of surgery in these areas, these are areas where skin cancer prevention is highly desirable.”

To test the thermal PDT hypothesis, Dr. Willey enrolled 20 patients with actinic keratoses (AKs) on the arms or legs. Despite differences in sun exposure on right versus left sides, she says, baseline lesion counts were similar on the heated and nonheated sides.

For each patient, she applied 20 percent ALA under occlusion (one hour) and randomly heated one extremity using an ordinary heating pad at a medium setting. “Then patients were exposed to the usual 10 J/cm² of blue light. Skin temperature was measured at baseline and every 15 minutes during incubation.

“Median skin temperatures after an hour of incubation reached around 39 degrees on the heated side and 29 degrees on the nonheated side (manuscript in preparation).” Heated limbs experienced more stinging during treatment, as well as post-treatment erythema and crusting, Dr. Willey says. Nevertheless, “If you use a cool-water spritzer and a fan during light exposure, the treatment is very well-tolerated.”

Temperature settings

To ensure that the treatment was safe and tolerable, Dr. Willey says she first applied a thermocouple under occlusion to her own leg and found that a heating pad set at low or medium for one hour (reaching 38 and 39 degrees Celsius respectively) was very easy to tolerate, but high settings that reached 42 degrees Celsius produced distinct discomfort. Though heating pad burns are fairly common, Dr. Willey adds, the study regimen appears safe as long as patients' limbs have normal sensory and vascular function.

“It is important to keep the heating pad covered, set on low or medium, and not to apply pressure,” she says.

Two months post-treatment, clearance rates of study patients’ heated extremities were approximately 88 percent, versus 66 percent on the unheated side. She credits the robust results on the unheated side to the fact that because the body circulates heat, the temperature of the unheated limb rose two or three degrees over baseline during treatment.

Six months post-treatment, heated limbs generally remained clear, Dr. Willey says, while she began to observe AK recurrences on unheated limbs. Moreover, she says that some study patients have remained clear up to 1.5 years post-treatment.

“Just throwing a heating pad on provides a substantial PDT reaction with just one hour of incubation. This makes the treatment beneficial for our patients and practical for our offices,” she says.

Study results prompted Dr. Willey to initiate a follow-up study using mapping templates that will help gauge the progress of each individual lesion for a year post-treatment. It’s scheduled for completion this fall.

Meanwhile, Dr. Willey also has treated a handful of patients using a space heater to warm the facial skin (while patients wear eye protection). When the facial skin reaches 38 degrees Celsius, she says patients can achieve as much porphyrin production in 20 minutes as they would in one hour at a skin temperature of 30 degrees Celsius. Though further research is needed, she says, such a regimen could increase both the efficiency and consistency of PDT.

Disclosures: Dr. Willey is an adviser for DUSA Pharmaceuticals, which sponsored the PDT study. She also has received honoraria from the company.