Aminolevulinic Acid (Levulan®) in Photodynamic Therapy of Actinic Keratoses

K. Lang, MD, K.-W. Schulte, MD, T. Ruzicka, MD and C. Fritsch MD

Hautklinik, Universitätslinikum Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany

ABSTRACT

The role of photodynamic therapy (PDT) in the treatment of in situ neoplasias and tumors of the skin is steadily increasing. Its principles of photodynamic action include an intratumoral enriched photosensitizer and light activation. Aminolevulinic acid (ALA) has demonstrated highest efficacy in topical PDT, and has become the most clinically useful. For actinic (solar) keratoses, topical ALA-PDT using Levulan® Kerastick™ (20% topical solution, DUSA Pharmaceuticals) is already postulated to be the treatment of choice. In December 1999, the US FDA approved this topical product for the treatment of actinic keratoses. Levulan® is well tolerated and leads to excellent cosmetic results with only minor side effects.

Key Words:
aminolevulinic acid, porphyrins, photosensitizer, photodynamic therapy, actinic keratoses

δ-Aminolevulinic acid HCl is an endogenous precursor of highly photosensitizing porphyrin metabolites. Normally, the synthesis of ALAis tightly controlled by feedback inhibition of the enzyme aminolevulinic acid synthase (ALA-S), presumably by intracellular heme levels.^1,2 Therefore, when exogenous ALA is provided to the cell through topical application, protoporphyrin IX accumulates by bypassing the rate limiting enzyme ALA-S.

In photodynamic therapy (PDT), light absorption by porphyrin metabolites, e.g., protoporphyrin IX, results in an excited state of the molecule and subsequent generation of reactive oxygen species, which can react further to form superoxide and hydroxyl radicals.³ The tissue-specific phototoxic effects resulting from local application of ALA and light irradiation are the basis of photodynamic therapy (PDT) for actinic keratoses (AKs) and other in situ neoplasias.

Pharmacology of ALA

The standard procedure of topical ALA-PDT for skin tumors involves the application of 10-20% ALA in an oil-in-water emulsion, which is then covered by an occlusive dressing to enhance the tissue penetration of the drug and to prevent undesired photobleaching of porphyrins by visible light.

Levulan® Kerastick™

ALA has been pharmaceutically included into Kerastick™ (20% topical solution, DUSA Pharmaceuticals).^4,5 Each Kerastick™ applicator has 2 sealed glass ampules containing 1.5ml hydroalcoholic solution vehicle and 354mg ALA. Schering AG, Berlin officially applied for Levulan® Kerastick™ to be used for the treatment of AK in Austria in 2001. Austria is acting as a reference member state for the European application. In the US it is marketed by Berlex Laboratories on behalf of DUSA.

Adverse-effects

Contraindications for PDT include cutaneous photosensitivity, porphyria, and allergies to ALA or to any of its components. Patients who have concomitant disorders that are provoked or aggravated by light should be evaluated cautiously. It is not known whether ALA or its metabolites are excreted in breast milk, therefore, caution should be exercised when treating women who are breastfeeding.

Following topical application of ALA, the treated site becomes photosensitive, and patients should be warned to avoid sunlight or bright indoor light (e.g., examination lamps, theater lamps, tanning beds, or lights at close proximity). Such exposure may result in a stinging and burning sensation and cause erythema and/or edema of the lesions.^2,6 Topical ALA treatment does not induce systemic accumulation of ALA or porphyrins.⁷

As a result of light exposure during PDT treatments, patients may experience burning pain, stinging, or itching, which is restricted to the illuminated area.^8-10 The discomfort will peak within the first minutes of irradiation. It may continue for several hours, though in a decreasing manner. Local anesthesia or intensive cooling can help to control the pain, especially when disseminated, large, ulcerative, or inflamed areas are treated.

The normal course of clinical response to PDT is usually distinguished by crusting, scaling, pruritus, and healing within 1-4 weeks.¹⁰ Urea preparations can be used to resolve dry crusts and accelerate re-epithelialization.^11,12 ALA produces very good cosmetic results, often superior to the outcome achieved by cryosurgery¹³, surgery, or topical chemotherapy. Generally, scar formation is minimal or absent. Rarely, residual hyperpigmentation or hypopigmentation of the treated area can occur.

Pharmacokinetics

The application of ALA in PDT for cutaneous disorders was introduced in 1990.¹⁴ The main advantage of this treatment is the absence of generalized cutaneous photosensitivity. The mechanisms of ALA uptake and accumulation in malignant and regenerative cells are not completely understood. Major responsibility for the tumor selectivity of ALA or synthesized porphyrins is the increased permeability of abnormal keratin layers in epithelial skin tumors. The active transport of the compound through plasma membranes was demonstrated in microorganisms and in cell culture.¹⁵ However, additional celltype dependent uptake mechanisms cannot be excluded. The optimal application time and concentration have already been elucidated by biochemical analyses of ALA-treated skin samples. Epithelial skin tumors such as basal cell (BCC) or squamous cell carcinomas (SCC) reveal maximum porphyrin levels 2-4 hours after topical ALA application.⁶

Light sources

In dermatology, the most commonly used irradiation sources include incoherent light sources that comprise red (570-750nm),⁹ green (545nm),¹⁰ or blue light (417nm,¹⁶ or 400-410nm¹⁷) and laser systems (e.g., argon pumped dye lasers). BLU-U™ has a nominal peak value of 417nm with a spectral range of 402- 432nm.¹⁸

Clinical Trials

In 1990, the topical application of 20% ALA to AKs, followed by a single exposure to the light of a filtered slide projector, resulted in a complete response (CR) of 90%.¹⁴ In the following years, other investigators, using more professional incoherent light sources, obtained a CR of 80-100% in AKs.^19-21 The CR rate of AKs located on the face and scalp was significantly higher (91%) when compared with keratoses on the trunk and extremities (45%). The often reported poor clinical response (<30%) of the thick hyperkeratotic lesions⁵ may have been due to ineffective penetration of ALA and consecutive insufficient production of porphyrin molecules.

In a randomized, multicenter, vehicle-controlled, investigatorblinded, light-dose ranging study, maximal therapeutic effects were obtained in ALA-treated AKs irradiated with blue light (BLU-U™, 417 nm) at a dose of 10J/cm² (10 mW/cm²).16 ALA solution (20%) or the vehicle only was applied to 2 lesions each, on the face and scalp of 36 patients. Lesions were exposed to 2, 5 or 10J/cm² of blue light (417nm) delivered at 3, 5 or 10mW/cm2, 14-18 hours after application. Eight weeks after treatment a CR was obtained in 66% of ALA-treated lesions versus 17% of those treated with vehicle and light (p < 0.001). The maximal response (80%) was seen in patients treated with the maximal dose of light (10 J/cm²). Non-responding lesions were re-treated at 8 weeks and by 16 weeks the CR was 85% in ALA-treated lesions. The efficacy of the higher light dose was confirmed in a second phase II study of 64 patients conducted with the same protocol.¹⁶

To establish the optimum concentration of ALA solution, a randomized, vehicle-controlled, investigator-blinded, multicenter study was carried out using ALA 2.5, 5, 10, 20, or 30% wt/vol and blue light (BLU-U™) at 10 J/cm² (10 mW/cm²).¹⁶ ALA was applied to lesions (site not specified) on 124 patients. There were significantly more CR (defined as clearance of 75% of lesions) in the groups treated with 10, 20 or 30% ALA than in the groups treated with 2.5 or 5%. A dose-response trend was evident with a plateau emerging at the 10, 20 and 30% dose levels. The researchers concluded that an ALA concentration of 20% produced the best response.

In phase III trials topical ALA 20% was effective in eradicating AKs of the face and scalp in the majority of patients. A total of 241 patients with 4-15 AKs each were enrolled in two randomized, vehicle-controlled, investigator-blinded, multicenter trials²² (see Table 1).

Table 1: Clinical Trial results using Levulan® and BLU-U™.
*Maximal response was seen in patients treated with the maximal light dose (10J/cm²).
**All patients showed multiple lesions. The clearance rate was higher for lesions on the face (78%) than on the scalp (50%).

Conclusion

Levulan® and BLU-U™ are very effective in the treatment of AKs. It is non-invasive and leaves the patients with excellent cosmetic results. The response of AKs to PDT equals the cure rates achieved by other topical treatment modalities, including the use of liquid nitrogen and chemical peels. In summary of the current data, ALA-PDT appears to be most efficient for the treatment of these in situ neoplasias.

References

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