Short ALA incubation coupled with blue light therapy yields effective, pain-free results.
For nearly two decades, dermatologists have been able to offer their patients a highly effective treatment for AKs thanks to Levulan, a liquid containing 5 aminolevulinic acid (5-ALA), to treat actinic keratoses (AKs) using photodynamic therapy (PDT). The FDA approved Levulan (5-ALA) based on a 14 to 18 hour incubation period following its application to the face or scalp.
Two significant factors clouded an otherwise bright advancement with this therapy: time and pain, and too much of both. Addressing those issues has been a primary focus for Maui-based dermatologist George Martin, M.D., a practicing clinician, clinical investigator, and internationally-recognized lecturer. He is founder and program chairman of MauiDerm, the internationally recognized dermatology meeting. Along with Dr. Ted Rosen, Dr. Martin discussed ALA PDT at Maui Derm 2015 in the presentation, Cutaneous Oncology, New and Novel Uses for “Field Therapies.”
OF LIGHT AND ALA
“Dermatology is exploding with new drugs and science,” Dr. Martin says. But scrutinizing the science may, in this case, have kept doctors from seeing the forest for the trees. Where PDT is concerned, less may be more.
Understanding the ALA PDT mechanism of action is critical to making innovations in treatment. Dr. Martin explains that PDT requires three components: a photosensitizer, an activating wavelength of light, and oxygen.
The 5-ALA is converted selectively inside cancerous and precancerous cells into a photosensitizer called protoporphyrin IX (PpIX), part of a heme synthesis pathway. The PpIX selectively accumulates inside the AKs. The PpIX is a photosensitizer, “so when you hit it with blue light, it creates a ton of free radicals that destroy AKs,” Dr. Martin explains.
Dr. Martin notes that the original studies were done applying the Levulan – the ALA – to the skin and waiting 14 to 18 hours to maximize the amount of protoporphyrin IX inside the precancerous cells, then using the blue light which selectively destroys the AKs.
Time and experience showed, however, that it was very impractical to apply a liquid to the skin, then wait 14 to 18 hours to bring the patient back into the office for blue light exposure. It just didn’t work logistically, Dr. Martin says. “It’s a convenience factor for the patient, some of whom come from 100 miles away. It’s just not practical.” So practitioners tended to shorten the ALA incubation period from the on-label 14 to 18 hours to 1, 2, or 3 hours – the so-called “short incubation” – then activate with the blue light.
A DUSA phase 2 study showed that the clearance rate with short incubations was about half that seen with longer incubation. The study data demonstrated that one short-incubation PDT treatment provided only part of the long-incubation efficacy; however, 80% individual AK clearance was achieved with at least two shorter-incubation treatments eight weeks apart.
“The results weren’t as good because you didn’t get as much protoporphyrin IX built up in AKs,” Dr. Martin says, “so you weren’t able to kill as many when you shortened the incubation... yet, that’s what everyone does.”
Even though the short incubations provided a practical improvement, there remained a tenacious downside. “An inherent problem with both long, overnight incubations and the short 1, 2, or 3 hour incubations is that both can be extremely painful for the patient,” Dr. Martin says. Two-thirds of the patients in the DUSA phase 2 study experienced what they described as moderate to severe pain.
“It doesn’t hurt until you turn the blue light on, at which point you create a photo-toxic reaction,” Dr. Martin says. “And that hurts.” He says that over the years, doctors tried everything from cooling fans, regional nerve blocks, topical anesthetics, and the use of narcotics to attempt to address the pain issue.
Still, the pain came out on top.
LET THE SUN SHINE
Dr. Martin became intrigued by a practice that took hold in Europe: so-called “daylight mediated PDT” using methyl ALA. “They put the methyl ALA on people’s faces,” Dr. Martin explains, “then about a half an hour later, put sunscreen on the patients and sent them outdoors for 1½ to 2½ hours of natural sunlight, letting the sunlight provide the activating wavelength of light.” The sunscreen blocked the harmful UVB rays below 400nm that cause sunburn, but allowed the activating longer wavelengths through – above about 400nm of light, then another peak of absorption around 630 – which activated the protoporphyrin IX produced by the methyl ALA.
Blue light – around 417nm – is the first and highest peak of absorption for PpIX. There is a secondary absorption peak at about 630nm – red light – and red light is the approved light for methyl ALA. There are differences, Dr. Martin notes. Red light penetrates much more deeply than blue light – about 5 mm vs. blue light’s 0.5 mm. So red light is actually preferable if one needs to target a deeper lesion in the skin.
“So instead of blue light they used sunlight, which has the two activating wavelengths of light. And what they found was they got incredible rates of clearance with little or no pain for the patient.”
Dr. Martin pondered how he could reproduce similar painless treatments in his practice. In Europe, there are guidelines for using daylight-mediated PDT, which is also attractive because the physician applies the liquid to the patient then sends the patient home. It frees up the patient’s time and also frees up the physician’s staff and facilities, as well as not requiring a purchased light source.
But Dr. Martin notes there are many unanswered questions, including the method’s practicality for varying geographic locations and/or weather conditions. “There are compliance issues, there are weather issues, and obviously, there are legal issues,” he says. “You have an unsupervised patient, and if something goes wrong, the dermatologist needs to understand that ‘daylight-mediated PDT’ is not the standard of care for PDT in the United States.”
In an effort to reproduce the pain-free results seen with daylight PDT in a controlled setting, Dr. Martin developed a method employing application of the ALA, and then waiting only 15 minutes later before activating it for an hour of blue light, “sort of reciprocal for the standard treatment,” Dr. Martin notes. He explains that his guiding principal was the hypothesis that a 15-minute incubation didn’t allow time for the PpIX building up in the AKs to diffuse into the surrounding tissue. This diffusion does occur with 1, 2, or 3 hour incubations, so the subsequent activating light non-specifically creates a phototoxic reaction in surrounding tissue which contains sensory nerve endings.
Theoretically, by not allowing the converted PpIX time to diffuse beyond the AK, the short 15-minute incubation prevents painful reactions. “So, by turning on the light after 15 minutes, you provide a more targeted therapy and less pain for the patient, because it’s more selective and not carpet-bombing surrounding nervous tissue,” Dr. Martin says. Additionally, he says, with the 15 minute incubation and then an hour under the blue light, “you’re blowing up the protoporphyrin IX as it is produced in the AKs, so you’re being very selective and not allowing time for large amounts of protoporphyrin IX to build up.”
In an in-office, proof-of-concept, split-face study, Dr. Martin treated one half of the face with painless PDT, and the other half with the standard short incubation (75 minute) approach. Although the efficacy on both sides was roughly equivalent, with approximately 50% of individual lesions clearing, “the pain scores were radically different,” he says, with the painless PDT side producing no pain, while the standard protocol side producing moderate pain.
Since the proof-of-concept study, Dr. Martin has treated over 100 patients using painless PDT, and in nearly all cases the patients remained pain-free. In over 2½ years of using it in his practice, Dr. Martin has not observed any downside to the painless PDT approach.
“We have enough data to convince ourselves – whether we use in-office painless PDT as monotherapy or in conjunction with pretreatments employing 5-flurouracil and imiquimod before PDT – it is in fact painless. So now we need to do large-scale clinical trials,” to prove efficacy, Dr. Martin says. Meanwhile, dermatologists may consider the off-label application of painless PDT for their growing population of AK patients. Technically, the standard of treatment is off-label anyway, Dr. Martin notes, “Because the on-label approval was for 14 to 18 hour incubation. So 1, 2, or 3 hour incubations are already off-label.”
If adjusting the times of incubation and the light application eliminates pain and is effective – not to mention more convenient and practical for patients and dermatology practices alike – then embracing it seems logical. It may very well be the next stage in the evolution of PDT.
Dr. Martin is a consultant and speaker for DUSA, Valeant and an advisor to LEO.