According to research reviewed by Gram, taking oral vitamin D or using vitamin D creams before photodynamic therapy significantly improves treatment success for actinic keratoses, especially thicker or stubborn lesions. A scoping review of 19 studies from 2009 to 2025 found that vitamin D pretreatments and the chemotherapy drug 5-fluorouracil showed the strongest evidence for enhancing PDT effectiveness by helping the light-sensitive drug penetrate deeper into damaged skin.
Photodynamic therapy, or PDT, is a light-based treatment for actinic keratoses, which are rough, scaly spots on skin caused by sun damage. However, PDT doesn’t always work well on thicker or stubborn lesions. Gram Research analysis of 19 studies found that using certain medications before PDT can help the treatment work much better. Vitamin D supplements taken by mouth and vitamin D creams applied to the skin showed the strongest results, along with a cancer drug called 5-fluorouracil. These pretreatments help the light therapy penetrate deeper into damaged skin and clear more lesions, especially in harder-to-treat cases.
Key Statistics
A scoping review of 19 studies published from 2009 to 2025 found that oral vitamin D and topical vitamin D analogs showed the most consistent improvements in photodynamic therapy response for actinic keratoses, particularly in grade II and thicker lesions.
According to research reviewed by Gram, 5-fluorouracil applied as a cream before photodynamic therapy demonstrated strong supporting evidence for improving treatment outcomes in actinic keratoses, with several studies showing increased fluorescence of the light-sensitive drug after pretreatment.
A systematic review of 19 studies found that corticosteroid pretreatment did not improve photodynamic therapy effectiveness for actinic keratoses, suggesting that reducing inflammation alone does not enhance the light therapy’s ability to clear lesions.
Research from 2009 to 2025 shows that urea and salicylic acid pretreatments generally increased photodynamic therapy efficacy to a level comparable to curettage, a mechanical scraping procedure for removing actinic keratoses.
The Quick Take
- What they studied: Whether using certain medications before photodynamic therapy (a light-based skin treatment) makes it work better for actinic keratoses, which are precancerous rough spots on sun-damaged skin.
- Who participated: The review analyzed 19 published studies from 2009 to 2025 involving patients with actinic keratoses who received photodynamic therapy with various pretreatment medications.
- Key finding: Oral vitamin D supplements and topical vitamin D creams or 5-fluorouracil applied before PDT significantly improved treatment success rates, particularly for thicker and more resistant lesions.
- What it means for you: If you have stubborn actinic keratoses that haven’t responded well to standard treatments, your dermatologist may recommend taking vitamin D or using specific creams before PDT to improve your chances of clearing the lesions. Results vary by individual, and your doctor should determine the best approach for your specific situation.
The Research Details
This was a scoping review, which means researchers searched three major medical databases (PubMed, Embase, and Scopus) for all published studies about using medications before photodynamic therapy for actinic keratoses. They looked for studies published between 2009 and 2025 that tested different pretreatment drugs and measured whether the therapy worked better afterward.
The researchers included 19 studies that met their criteria. These studies tested many different pretreatment options, including oral vitamin D, vitamin D creams, 5-fluorouracil (a chemotherapy drug), retinoids (vitamin A derivatives), urea, salicylic acid, corticosteroids, diclofenac (an anti-inflammatory), and ingenol mebutate (a plant-derived compound). The studies measured success by looking at how many lesions cleared completely, whether they came back, how much fluorescence (glowing) the lesions showed under special light, and what side effects occurred.
A scoping review is useful for summarizing what’s known across many different studies, but it doesn’t combine the data statistically like a meta-analysis does. This approach helped the researchers identify patterns and see which pretreatments showed the most promise.
Photodynamic therapy works by using a light-sensitive drug that gets activated by specific wavelengths of light to destroy abnormal skin cells. However, the drug sometimes can’t penetrate thick or stubborn lesions effectively, which reduces treatment success. By understanding which pretreatments help the drug work better, dermatologists can improve outcomes for patients with difficult-to-treat lesions and potentially prevent progression to skin cancer.
This review examined published studies from a 16-year period, which provides a good overview of the field. However, the studies varied significantly in their methods, dosages, treatment schedules, and how they measured results, making direct comparisons difficult. The review included only English-language studies, which may have missed relevant research published in other languages. The quality of individual studies likely varied, though the review doesn’t provide detailed quality assessments of each included study.
What the Results Show
Oral vitamin D supplements and topical vitamin D analogs (specially designed vitamin D compounds) showed the most consistent improvements in photodynamic therapy response. These pretreatments were especially effective for grade II lesions (moderate-thickness actinic keratoses) and thicker, more resistant lesions that typically respond poorly to standard treatment.
The chemotherapy drug 5-fluorouracil, applied as a cream before PDT, also demonstrated strong supporting evidence for improving treatment outcomes. Several studies showed that these pretreatments increased the fluorescence of protoporphyrin IX, which is the light-sensitive molecule used in photodynamic therapy. This increased fluorescence suggests the drug penetrates better into the damaged skin tissue.
Retinoids (vitamin A derivatives) showed mixed results across studies, meaning some studies found benefits while others did not. Urea and salicylic acid generally improved treatment effectiveness to a level comparable to curettage, which is a mechanical scraping procedure. These findings suggest multiple pathways can enhance PDT effectiveness, though some work better than others.
Corticosteroid pretreatment did not appear to improve photodynamic therapy effectiveness, suggesting that reducing inflammation before treatment doesn’t enhance the light therapy’s ability to clear lesions. Diclofenac, an anti-inflammatory drug, showed limited short-term benefits but may reduce lesion burden over longer periods, though the evidence was less robust. Ingenol mebutate, a plant-derived compound, only showed a statistically nonsignificant reduction in actinic keratoses, meaning the improvement could have been due to chance rather than the treatment itself.
This review synthesizes evidence from studies conducted over 16 years, representing the most current understanding of pharmacologic pretreatments for photodynamic therapy in actinic keratoses. The findings align with the biological principle that improving drug penetration into thicker lesions should enhance treatment efficacy. The strong evidence for vitamin D pretreatments is particularly noteworthy, as vitamin D has known effects on skin cell differentiation and immune function. The mixed results with retinoids suggest that not all skin-active compounds enhance PDT equally, which may reflect differences in how they affect skin barrier function and drug penetration.
The 19 studies included in this review varied significantly in their study design, pretreatment regimens, dosages, treatment schedules, and how they measured outcomes. This heterogeneity makes it difficult to directly compare results across studies or draw definitive conclusions about which pretreatment works best. The review included only English-language publications, potentially missing relevant research published elsewhere. Individual study quality assessments were not detailed in the review. Most studies were relatively small, and long-term follow-up data were limited. The review did not assess publication bias, meaning studies with positive results may be overrepresented compared to studies that found no benefit.
The Bottom Line
If you have actinic keratoses that haven’t responded well to standard photodynamic therapy, discuss with your dermatologist whether pretreatment with oral vitamin D or topical vitamin D analogs or 5-fluorouracil might improve your results. The evidence is strongest for these three options, particularly for thicker or resistant lesions. Avoid corticosteroid pretreatment, as it does not appear to enhance PDT effectiveness. Other options like retinoids, urea, or salicylic acid may be considered, though evidence is less consistent. These recommendations should be personalized based on your specific lesions, skin type, and medical history.
Dermatologists treating patients with actinic keratoses should consider these findings when standard photodynamic therapy has not been effective. Patients with multiple or thick actinic keratoses, particularly those on sun-exposed areas, may benefit from discussing pretreatment options with their doctor. People with a history of skin cancer or precancerous lesions should be aware that enhanced PDT through pretreatment may improve their outcomes. This information is less relevant for patients with thin, easily treated lesions that respond well to standard PDT without pretreatment.
Pretreatment regimens typically last from several days to several weeks before photodynamic therapy is performed. Improvements in lesion clearance may be visible within weeks to months after treatment, though complete healing can take several months. Long-term benefits, such as reduced recurrence rates, typically become apparent over 6 to 12 months of follow-up. Individual results vary based on lesion characteristics, pretreatment type, and skin type.
Frequently Asked Questions
What is photodynamic therapy and how does it treat actinic keratoses?
Photodynamic therapy uses a light-sensitive drug applied to the skin, then activates it with specific wavelengths of light to destroy abnormal skin cells. The drug preferentially accumulates in precancerous lesions like actinic keratoses, and the light causes it to produce reactive molecules that kill the damaged cells while leaving healthy skin relatively unharmed.
Why do some actinic keratoses not respond well to photodynamic therapy?
Thicker or stubborn actinic keratoses often have a dense outer layer that prevents the light-sensitive drug from penetrating deeply enough to reach all the abnormal cells. This reduced penetration means less drug accumulates in the lesion, making the light therapy less effective at destroying the precancerous tissue.
Which pretreatment medications work best before photodynamic therapy?
Oral vitamin D supplements and topical vitamin D creams showed the strongest evidence for improving photodynamic therapy outcomes, particularly for thicker lesions. The chemotherapy drug 5-fluorouracil applied as a cream also demonstrated strong benefits. These pretreatments help the light-sensitive drug penetrate deeper into damaged skin.
How long does pretreatment take before photodynamic therapy?
Pretreatment regimens typically last from several days to several weeks before photodynamic therapy is performed, depending on the specific medication and dosage prescribed by your dermatologist. Your doctor will provide specific instructions on when to start pretreatment and when to schedule your PDT appointment.
Are there any pretreatments I should avoid before photodynamic therapy?
Corticosteroid pretreatment did not improve photodynamic therapy effectiveness in studies reviewed, so it should not be used specifically to enhance PDT. Discuss with your dermatologist which pretreatments are appropriate for your specific lesions and medical history, as some options may not be suitable for all patients.
Want to Apply This Research?
- If using a pretreatment medication before photodynamic therapy, track daily medication adherence and photograph the treatment area weekly to monitor lesion appearance, redness, and healing progression. Record the date of PDT treatment and note any side effects or changes in lesion appearance in the weeks following treatment.
- Set daily reminders to apply topical pretreatment creams or take oral vitamin D supplements at the prescribed time before your scheduled photodynamic therapy. Document your treatment schedule in the app to ensure you complete the full pretreatment course as recommended by your dermatologist.
- Create a photo timeline in the app showing your lesions before pretreatment, before PDT, and at regular intervals after treatment (weekly for the first month, then monthly for 6 months). Track any recurrence of lesions and compare your results to your baseline. Share this documentation with your dermatologist at follow-up appointments to assess treatment effectiveness.
This article summarizes research findings and should not replace professional medical advice. Photodynamic therapy and pretreatment medications carry potential risks and side effects that vary by individual. Before starting any pretreatment regimen or photodynamic therapy, consult with a board-certified dermatologist who can evaluate your specific skin condition, medical history, and medications. The effectiveness of pretreatments varies among individuals, and what works best for one person may not work equally well for another. This information is current as of the publication date but medical recommendations may change as new evidence emerges.
This research translation is published by Gram Research, the science division of Gram, an AI-powered nutrition tracking app.