ALA AND METHYL-ALA (MAL)
TOPICAL PHOTOSENSITISERS FOR SKIN PDT
Unlike the IV-administered Photofrin that causes weeks of photosensitivity, ALA and MAL are applied as cream directly to skin lesions โ converted to an active photosensitiser only in pre-cancerous cells, activated with red light after 3โ4 hours, and causing photosensitivity for just 24โ48 hours. Skin PDT has become a standard outpatient treatment for actinic keratosis and selected skin cancers.
analyticsAt a Glance
- check_circleTopical cream application โ not IV injection; suitable for outpatient clinic treatment
- check_circleApplied for 3โ4 hours; activated with red LED light at 630โ635 nm
- check_circlePhotosensitivity only 24โ48 hours โ dramatically shorter than Photofrin
- check_circleStandard of care for actinic keratosis; approved alternative for BCC and Bowen's disease
What Are ALA and MAL?
ALA (5-aminolaevulinic acid) and MAL (methyl aminolevulinate) are prodrugs โ they are not themselves photosensitisers, but are converted by cancer cells into protoporphyrin IX (PpIX), which is the actual photoactive molecule. This biochemical conversion step is the basis of their selectivity.
โALA and MAL work with the cancer cell's own biochemistry. Abnormal skin cells convert them to a photosensitiser much more efficiently than normal cells โ building selective toxicity on the cell's own metabolic activity.โ
5-ALA: The Original Topical Agent
5-aminolaevulinic acid (5-ALA) is a naturally occurring intermediate in the haem biosynthesis pathway. Applied topically as a cream or gel, it is taken up preferentially by dysplastic and cancerous keratinocytes and converted to protoporphyrin IX (PpIX) โ which accumulates and fluoresces red-pink under Wood's lamp, confirming uptake. Commercially available as Levulan (topical solution/sticks) and other formulations.
MAL (Methyl-ALA): The More Lipophilic Ester
Methyl aminolevulinate (MAL, marketed as Metvix) is the methyl ester of ALA. The methyl group makes it more lipophilic โ improving penetration through the stratum corneum and into thicker or more scaly lesions. MAL has EMA approval for actinic keratosis, superficial BCC, nodular BCC, and Bowen's disease. Studies suggest better penetration for nodular lesions vs standard ALA.
Approved Skin PDT Indications
ALA and MAL are approved for the following dermatological conditions โ with strong evidence bases and established treatment protocols.
| Condition | Agent | Evidence / Approval | PDT Role |
|---|---|---|---|
| Actinic Keratosis (AK) | ALA and MAL | FDA (ALA) and EMA (MAL) approved; first-line standard | Preferred for field cancerisation โ treating multiple lesions simultaneously |
| Superficial Basal Cell Carcinoma | MAL (Metvix) | EMA approved; NICE-recommended in UK | Alternative to surgery; excellent cosmetic outcome; lower recurrence for well-selected cases |
| Nodular Basal Cell Carcinoma (<2 mm depth) | MAL | EMA approved with conditions | Suitable for selected thin nodular BCC; pre-treatment curettage improves penetration |
| Bowen's Disease (SCC in situ) | ALA and MAL | EMA approved; BAD guidelines recommend | Preferred for large, multiple, or anatomically difficult lesions where surgery is challenging |
| Actinic Cheilitis (lip AK) | ALA | Good evidence; off-label in some regions | Treatment of pre-malignant lip changes; preserves lip architecture |
The Skin PDT Procedure โ Step by Step
Standard clinic-based MAL/ALA-PDT procedure for actinic keratosis and superficial skin cancer.
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Step 1: Lesion Preparation
The treatment area is gently cleaned and any scale, crust, or thick keratin is removed by light curettage or emery paper. For nodular BCC, curettage to the base of the tumour is performed under local anaesthetic before cream application โ improving photosensitiser penetration into thicker lesions.
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Step 2: Cream Application
MAL or ALA cream is applied 1 mm thick to the lesion and 5โ10 mm of surrounding tissue. The treated area is covered with an occlusive dressing (Tegaderm or similar) to prevent drying and maximise penetration. Patient waits in the clinic or goes home; the cream remains in place for 3 hours (MAL) or up to 6 hours (some ALA protocols).
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Step 3: Optional Fluorescence Check
Under Wood's lamp (UV illumination), protoporphyrin IX in the treated tissue fluoresces pink-red โ confirming drug uptake before light delivery. Non-fluorescing lesions may benefit from re-preparation or longer incubation.
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Step 4: Red LED Light Delivery
The occlusive dressing is removed. A red LED panel (typically 630 nm) is positioned 5โ10 cm above the treatment field and delivers 37โ75 J/cmยฒ over 7โ8 minutes. Stinging or burning during light delivery is common โ managed with cold air cooling.
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Step 5: Post-Treatment Care
Treatment area will be red and inflamed for 2โ7 days. Patient avoids sun and bright light for 24โ48 hours (treated skin only โ full-body avoidance not required for topical agents). Emollient cream applied to the treated area. A second treatment session 1 week later is standard for most indications to maximise clearance.
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Step 6: Review and Response Assessment
Clinical assessment at 3 months evaluates lesion clearance. Complete response rates: actinic keratosis 70โ90%; superficial BCC 60โ85% at 3 months (declining slightly with longer follow-up). Persistent or new lesions can be retreated.
Daylight PDT: An Important Variant
Conventional PDT uses an artificial LED lamp for light delivery. Daylight PDT is a simpler variant for actinic keratosis that uses ambient outdoor daylight as the light source โ significantly more patient-friendly and suitable for widespread field cancerisation.
How Daylight PDT Works
A standard SPF 30+ sunscreen is applied to the entire face 30 minutes before the ALA or MAL cream. The cream is applied to the treatment field (without occlusion) and the patient walks outdoors into daylight for 2 hours. The continuous low-level outdoor light activates the photosensitiser gradually throughout the skin as it accumulates.
Why the Sunscreen Paradox Matters
Counterintuitively, sunscreen is applied before the photosensitiser cream โ not to block PDT, but to prevent conventional (UV-driven) sunburn from skin unprotected during the 2-hour outdoor exposure. The sunscreen blocks UV but allows the visible red wavelengths that activate PpIX to pass through.
Advantages: Less Pain, Equivalent Efficacy
Daylight PDT for actinic keratosis causes substantially less pain and discomfort than conventional lamp PDT โ because the activation is gradual rather than intense. Multiple randomised trials show equivalent clearance rates for AK treatment. Many patients strongly prefer daylight PDT for this reason.
Limitation: Weather-Dependent
Daylight PDT requires adequate outdoor light โ typically >10,000 lux, which corresponds to overcast daylight in most temperate climates. It is not suitable on heavily overcast or rainy days, in winter months at high latitudes, or for indoor-confined patients. Conventional lamp PDT remains necessary in these situations.
ALA vs MAL: Choosing Between the Two
Both achieve similar outcomes in most indications; the choice depends on indication, lesion type, and local availability.
5-ALA
- FDA Approved for AK (USA)Levulan Kerastick holds FDA approval for actinic keratosis on the face and scalp.
- Wider Global AvailabilityMultiple manufacturers; more widely available in diverse market formulations.
- Lower Cost in Many MarketsGenerally less expensive than branded MAL products.
- Established Daylight PDT ProtocolsBoth ALA and MAL are used in daylight PDT; robust protocols for ALA exist.
MAL (Metvix)
- EMA Approved for BCC and Bowen'sMetvix holds European approval across more skin cancer indications than ALA.
- Better Penetration into Thicker LesionsMore lipophilic structure improves penetration through scaly or thick lesions.
- Standard Cream FormulationConsistent cream formulation; standardised application protocol across clinics.
- More Evidence for Nodular BCCThe nodular BCC data is largely MAL-based โ preferred agent for this indication.
Explore the PDT Knowledge Base
Related PDT topics and resources.
Frequently Asked Questions
Common questions about ALA and MAL skin PDT.
About the Treatment
How painful is skin PDT?
Conventional lamp-based ALA/MAL-PDT causes a stinging or burning sensation during the light delivery phase โ often described as a pricking or heat sensation. This is usually manageable with cold air cooling (a cold air blower directed at the treatment area during light exposure). Severity varies by location: face and scalp PDT is typically well tolerated; shin and lower leg PDT can be more uncomfortable due to less vascular tissue. Daylight PDT is substantially less painful than conventional lamp PDT for equivalent efficacy in AK.
How many treatments will I need?
Standard protocols for actinic keratosis and most skin cancer indications use 2 treatment sessions 1 week apart. Complete clearance rates at 3 months are substantially higher with two sessions vs one. Some patients with very extensive field cancerisation may need repeat courses annually. Your dermatologist or PDT-treating clinician determines the appropriate schedule based on clearance assessment at 3 months.
Can skin PDT be performed on the scalp?
Yes. The scalp is one of the most common treatment areas for actinic keratosis PDT, particularly in bald or thinning-hair areas with high cumulative sun exposure. Hair should be parted to allow cream and light access to the scalp skin. Conventional lamp PDT and daylight PDT are both feasible on the scalp.
How CancerFax Helps
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Actinic Keratosis, BCC, or Bowen's Disease? PDT May Be Your Best Option.
For patients with widespread actinic keratosis, superficial BCC, or Bowen's disease โ particularly on the face, scalp, or other cosmetically sensitive areas โ topical ALA or MAL PDT can provide excellent field treatment. Our team can identify specialist PDT dermatology centres for your case.
For informational purposes only. Skin PDT suitability requires evaluation by a qualified dermatologist or skin cancer specialist.