The pain associated with the conventional PDT treatment for superficial cutaneous tumors using topical ALA and its derivatives is severe and can often be intolerable. The requirement of analgesics, and in the case of large and numerous lesions sometimes anesthesia, is a serious drawback of this otherwise highly useful therapy. Treatment has frequently been interrupted or abandoned due to pain. Therefore, a reliable, simple and inexpensive method to greatly reduce or eliminate pain associated with PDT using ALA and its derivatives represents significant clinical benefit.
This retrospective analysis of off-label treatments of topical ALA-PDT of cancerous skin lesions, which employed a two-step irradiance protocol to control light-treatment-associated pain, was carried out to assess the validity of this approach for the general dermatologic practice. The goal was to determine if we could fix the amplitude and the duration of the initial irradiance based on previous experience and still retain the benefits – pain reduction and treatment efficacy without significant increase in treatment time – without the complexity of performing real time optical measurements on each patient. The analysis has revealed that for most lesions an initial irradiance at 40 mW/cm2 for 20 J/cm2, followed by an irradiance at 150 mW/cm2 for the remainder of the total required light dose, causes no or minimal pain. For lesions located close to bone or heavily innervated areas (H&N, tibia), an initial irradiance of 30 mW/cm2 for 20 J/cm2 is recommended. The light dose of 20 J/cm2 for the initial low irradiance interval was adopted from our earlier prospective study because it had been found to photobleach 80-90% of PpIX. The elimination of direct monitoring of PpIX photobleaching during PDT for each patient was a critically important aspect of this study. The fact that treatment parameters derived previously appear to be generally applicable enables the protocol to be adopted widely by dermatologic clinics, few of which are capable of integrating spectroscopic monitoring into routine use.
An extensive review of pain associated with ALA-PDT for various skin diseases, including psoriasis, acne, actinic keratoses (AKs) and BCC, has been published by Warren et al.(4
), covering 43 publications between 2000 and 2008. Pain usually commences immediately upon the irradiation of the lesion and tends to level off with time of light exposure. Treatment parameters such as PpIX fluorescence, wavelength of light, light dose and light dose rate have all been investigated with regard to pain, with often-conflicting results. Approaches to pain control have also been investigated and it was concluded that cooling of the lesion during irradiation was so far most effective, although this provided only limited relief (4
The relationship between irradiance, which in the majority of published studies ranged from 50 to 150 mW/cm2
, and pain has been investigated in several studies. Ericson et al. (15
) found no difference in pain levels between 30 and 75 mW/cm2
in AKs treated with ALA-PDT. On the other hand, Wiegell et al. (16
), using the ALA derivative (methylaminolevulinic acid (MAL), found significantly higher pain scores with 68 mW/cm2
than 34 mW/cm2
in patients with acne. In a randomized study of MAL-PDT for AKs, comparing pain levels with two different light sources (irradiances of ~50-75 mW/cm2
) and cooling sprays, von Felbert reported median pain levels of VAS 50-80, using a VAS scale of 0-100 (8
). Cottrell et al. (14
) demonstrated a clear relationship between irradiance and pain when using ALA-PDT and 633 nm wavelength irradiation in sBCC. Taking advantage of the fact that the origins of ALA/PDT-induced pain are photochemical rather than photothermal and exploiting the more efficient photobleaching of PpIX at relatively low irradiance (14
), they devised an irradiation schema that employed low irradiance until 80-90% of PpIX was photobleached (within 3-8 min), followed by high irradiance until the full light dose (200 J/cm2
) was delivered. Starting irradiances below 60 mW/cm2
resulted in most cases in minimal pain throughout the treatment without the use of analgesics, and with good clinical responses. Our current retrospective analysis of this off-label use of ALA/PDT revealed remarkably low pain levels, with an overall median VAS score of 1.0 for both irradiance levels.
Since the goal of our report was to validate a two-step irradiance approach in the day-to-day clinical practice, with fewer restrictions on lesion size and number, irradiances in some cases were adjusted depending on the clinician's expectation based on prior experience, lesion location, patient's anxiety levels, etc. One caveat regarding these data is the fact that the number of lesions was not distributed evenly among patients, i.e. a few patients provided a large number of the evaluated lesions, which might have influenced the analysis. Nevertheless, the analysis confirms the low irradiance pain levels reported by Cottrell (14
). We note, however, that in the current study, all but two of the lesions treated with an initial irradiance of 50 mW/cm2
scored VAS 3 or higher, well above the median of 1, suggesting that a more reliable estimate of the pain threshold irradiance is closer to 50 mW/cm2
These exceptionally low pain scores may be somewhat influenced by the fact that, except for three Bowen's disease lesions, all lesions analyzed were BCCs. The type of skin disease treated has been shown to be a strong predictor of pain. Psoriasis likely produces the highest levels of pain (4
) compared to other lesions. Thus, a different, lower initial irradiance may be necessary for ALA-PDT in these patients. Grapengiesser et al. (19
) concluded that BCC's, which had a mean VAS score of 3.5 with irradiance of 76.5 mW/cm2
, generated less pain than AKs, although the field size treated was much larger with AKs than BCC's, possibly confounding any conclusion. In the current study lesion size did not appear to significantly influence pain (data not shown). Pain levels also did not significantly differ between sBCC and nBCC, or in regards to the number of lesions.
Lesion location proved to be a strong predictor of pain, confirming previous published findings (19
). Patients with treated areas with less subcutaneous tissue and/or which were well innervated, such as the face or pretibia, experienced the greatest level of pain, requiring either irradiance adjustment or anesthesia. In comparison to prior work (authors’ unpublished experience), however, where most lesions required analgesia with continuous 150 mW/cm2
treatment, analgesics were required for only 5 of 127 lesions treated with the two-step protocol. The literature is conflicted regarding the pain reported by men vs. women in response to ALA-PDT. Grapengiesser et al. (19
) described gender differences, with men experiencing higher levels compared to females. Other studies have suggested that gender along with age is a poor predictor of pain (5
). The results from our study, albeit limited, suggested slightly higher pain scores for females. This outcome, however, may reflect lesion location rather than a gender-based difference in pain levels. Thirteen lesions in pain-prone areas such as the face and scalp presented on female patients.
The clinical outcomes reported here for a single PDT treatment per lesion, with no limit on lesion size, compare well to most published results, showing the efficacy of ALA-PDT for sBCC's with 84% CCR at 6 month follow-up. Most partial responses represented >90% lesion clearance, with the remaining areas easily controllable with a second PDT exposure. Treatment of nBCC's was more disappointing with 36% CCR, also comparable to prior studies and likely related to the thickness of nBCC's and the difficulties associated with depth of penetration of photosensitizer along with limited penetration of the red light. The low irradiance portion of the treatment is not expected to adversely affect outcomes. In fact, low irradiance has been related to increased PDT efficacy (21
) due to improved maintenance of tissue oxygenation during irradiation (10
). Langmack et al. (23
) achieved 84% CCR at 1 year in sBCC treated with ALA-PDT with only 12.6 J/cm2
at 7 mW/cm2
, requiring 30 min of light exposure. However, only 5 of 32 lesions in that study were treated only once. Most lesions were treated twice, and 6 needed 3 or more treatments. Since any reduction in irradiance requires additional exposure time for a given light dose, higher light doses are difficult to achieve in clinical practice because of clinical time limitations, especially in patients with numerous lesions. The approach outlined in this report facilitates the effective delivery of even high light doses with minimal prolongation of treatment time and minimal pain. Indeed from a PDT dosimetry perspective, it may be interesting to consider stepped irradiance protocols in other clinical settings where pain is not an issue. An initial low irradiance would preserve tissue oxygen and facilitate rapid photosensitizer bleaching. Because oxygen depletion results from the rate of photon absorption by the photosensitizer and not irradiance per se
, a subsequent higher irradiance would be an efficient means of delivering increased fluence without oxygen depletion. We are aware of only one preclinical evaluation of a stepped irradiance protocol (24
Although our PDT treatments were performed with an optical-fiber-coupled laser, a two-step irradiance protocol may be implemented easily in centers using an LED array. With the Aktilite lamp, for example, we have implemented a two-step schedule by attaching a removable, mounted sheet of neutral density film to the LED head. The initial low irradiance interval is performed with the attenuating film in place. The second, higher irradiance is accomplished by removing the film from the beam path.
In conclusion, we have validated a simple approach to minimize the pain experienced by patients undergoing topical ALA-PDT for cutaneous cancers. While this report has some limitations, i.e. uneven distribution of lesions among patients, short follow-up periods and lack of histopathological analysis, taken together with our earlier prospective study, we conclude that the protocol offers significant benefit to patients. It does not require any special equipment, reduces cost by eliminating/reducing the use of analgesics, does not unduly increase treatment time, and, importantly, permits tailoring treatments to each individual patient's needs. It thus allows delivery of larger light doses under these beneficial conditions, which represents a significant clinical improvement and may help to overcome one of the obstacles to broader clinical dissemination of this attractive therapeutic option.