Actinic Keratosis
Conditions
Keywords
PDT, skin cancer, calcipotriol
Brief summary
In topical photodynamic therapy (PDT) for non-melanoma skin cancers, a photosensitizing prodrug, 5-aminolaevulinic acid (ALA) or its methylated ester, methyl aminolevulinate (MAL), is converted to the endogenous photosensitizer protoporphyrinIX (PpIX). Reduced response rates are observed in thicker skin lesions, which may be due to insufficient PpIX accumulation within the target tissue. To enhance PpIX production,several physical and chemical pretreatments have been suggested. One of the chemical substances proposed to stimulate PpIX production is vitamin D because of its ability of being a keratinocyte pro-differentiating hormone. Based on in vitro and in animal model studies, we propose to study the potential impact of patient vitamin D pre-treatment in AK response to MAL-PDT.
Detailed description
A randomized, controlled Split -scalp study with Calcipotriol Assisted MAL-PDT versus conventional MAL-PDT for actinic keratosis (AK) is proposed. Twenty patients ( male gender only) with symmetrically distributed multiple AK lesions on the scalp will be included. Patients must have at least five AKs per field to be eligible. After simple randomization, one half of the scalp will be treated with Calcipotriol ointment 50 mcg/g (Daivonex, Leo Pharma, Denmark) for 15 consecutive days. After this period, the entire scalp will be submitted to topical PDT with Methylaminolevulinate 16% (Metvix, Galderma France) under occlusion for 90 minutes and then, illuminated with a light source consisting of a Light Emitting Diode device (LED) at 635 nm ( Aktilite - Photocure, Norway). The total light dose will be 37J/cm2. Immediately before and after illumination with LED, measurements of the fluorescence intensity will be taken in 3 isolated spots in both sides of the scalp with a spectroscopy deviceUSB 2000+ ( Ocean Optics ® - Dunedin, Fl, USA). AK lesions will be counted and mapped by a dermatologist not involved in the study before and after 3 months. All patients will be advised to apply sunscreens 50 + 3x/day for the following 7 days after the procedure. A 0-10 Visual Analogue Scale (VAS) will be used to measure the pain intensity during the illumination. Records will be taken after 90 days and compared between sides: side effects, AK lesion response and pain level intensity. Also, a long term follow up will be provided at 6 and 12 months after.
Interventions
OTHERConventional MAL-PDT
Curettage of lesions and application of MAl cream 16% for 90 minutes under occlusion followed by LED 635 nm illumination at 37 J/cm2 total dose
OTHERCalcipotriol assisted MAL-PDT
Calcipotriol 50 mcg/g for 15 days prior to PDT. Curettage of lesions and application of MAl cream 16% for 90 minutes under occlusion followed by LED 635 nm illumination at 37 J/cm2 total dose
Sponsors
University of Sao Paulo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
50 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
* male gender * at least six AKs per field
Exclusion criteria
* history of photosensitivity related disorders * active infectious disease, * immunosuppression * laser or any cosmetic treatment in the previous 6 months * other topical agents in the treatment area such as retinoids, 5-fluorouracil,imiquimod or diclofenac sodium in the previous 3 months * allergy to MAL or excipients of the cream * poor patient compliance.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes From Baseline in Actinic Keratosis - Lesion Base Count. | Change from baseline, 90 days, 180 days and 12 months after the PDT | To compare the efficacy of topical PDT alone versus Calcipotriol assisted PDT for AKs on the scalp. The values in the data table represent the mean (+sd) number of lesions on each side at 3, 6 and 12 months post intervention. Lesion counts include lesions that have not been cleared and also newly emerged lesions ( if new lesions emerge on the treated field) At baseline: number of AKs was 290 on the CAL-PDT side and 284 on the conventional side. |
| Percentage of Actinic Keratosis (AK) Lesions Cleared | Change from baseline, 90 days, 6 months and 12 months after PDT | AK clearance after PDT and comparison between the sides The values in the data table represent the percentage of AK clearance on each side at 3, 6 and 12 months post intervention. At baseline: 290 on the CAL-PDT side and 284 on the conventional side. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pain Scores Immediately Post Illumination | immediately after intervention | Measurement of pain during LED illumination and comparison between the sides with a visual analogue scale (VAS), considering 0 as absence of pain and 10 as the most severe pain. At baseline, before the illumination, there is an absence of pain, which means Score 0 (zero) for all participants before the procedure. Pain is reffered during and after the illumination and measured with the VAS scale, reported by each patient. |
| Change From Baseline in Fluorescence Intensity of PPIX | Baseline and 10 minutes after illumination | Measurement of PPIX fluorescence on both sides of the scalp before and immediately after LED illumination PpIX fluorescence was measured in three different spot areas on the scalp before and immediately after PDT on each side. The measurements were taken noninvasively in the areas where PpIX fluorescence was more intense, with a handheld fluorescence photometer (USB 2000+ spectroscopy device; Ocean Optics, Dunedin, FL, U.S.A.). The photometer illuminates a circular skin area with a diameter of 1 cm with blue light (400-420 nm), matching the Soret band of PpIX at 405-420 nm. By measuring excitation wavelengths at 600- 700 nm, the corresponding red PpIX fluorescence intensity at 633 nm is detected. Measurements were taken in arbitrary units. The mean PpIX fluorescence value for each side was calculated before and after the treatment. |
Countries
Brazil
Participant flow
Recruitment details
All twenty patients completed the 12 -month study. Patients were male, Fitzpatrick skin types I-III and mean age 73.8 years (range 54-89).
Participants by arm
| Arm | Count |
|---|---|
| All Participants Conventional topical PDT with Methylaminolevulinate 16% in one half of the scalp with multiple AKs.
Conventional MAL-PDT: Curettage of lesions and application of MAl cream 16% for 90 minutes under occlusion followed by LED 635 nm illumination at 37 J/cm2 total dose
Calcipotriol ointment 50 mcg/g applied once a day for 15 consecutive days in one half of the scalp, before Conventional topical PDT Calcipotriol assisted MAL-PDT: Calcipotriol 50 mcg/g for 15 days prior to PDT. Curettage of lesions and application of MAl cream 16% for 90 minutes under occlusion followed by LED 635 nm illumination at 37 J/cm2 total dose | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 15 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| number of AKs at baseline CAL-PDT side | 290 number of lesions |
| number of AKs at baseline CAL-PDT side grade I | 223 number of lesions |
| number of AKs at baseline CAL-PDT side grade II | 67 number of lesions |
| number of AKs at baseline Conventional PDT | 284 number of lesions |
| number of AKs at baseline Conventional PDT grade I | 222 number of lesions |
| number of AKs at baseline Conventional PDT grade II | 62 number of lesions |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 20 Participants |
| Region of Enrollment Brazil | 20 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 20 | 12 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
Changes From Baseline in Actinic Keratosis - Lesion Base Count.
To compare the efficacy of topical PDT alone versus Calcipotriol assisted PDT for AKs on the scalp. The values in the data table represent the mean (+sd) number of lesions on each side at 3, 6 and 12 months post intervention. Lesion counts include lesions that have not been cleared and also newly emerged lesions ( if new lesions emerge on the treated field) At baseline: number of AKs was 290 on the CAL-PDT side and 284 on the conventional side.
Time frame: Change from baseline, 90 days, 180 days and 12 months after the PDT
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Calcipotriol Assisted MAL-PDT | Changes From Baseline in Actinic Keratosis - Lesion Base Count. | 3 months outcome | 1.15 lesions | Standard Deviation 0.99 |
| Calcipotriol Assisted MAL-PDT | Changes From Baseline in Actinic Keratosis - Lesion Base Count. | 6 months outcome | 1.15 lesions | Standard Deviation 0.93 |
| Calcipotriol Assisted MAL-PDT | Changes From Baseline in Actinic Keratosis - Lesion Base Count. | 12 months outcome | 1.35 lesions | Standard Deviation 1.04 |
| Conventional MAL-PDT | Changes From Baseline in Actinic Keratosis - Lesion Base Count. | 3 months outcome | 2.65 lesions | Standard Deviation 1.35 |
| Conventional MAL-PDT | Changes From Baseline in Actinic Keratosis - Lesion Base Count. | 6 months outcome | 2.60 lesions | Standard Deviation 1.14 |
| Conventional MAL-PDT | Changes From Baseline in Actinic Keratosis - Lesion Base Count. | 12 months outcome | 3.20 lesions | Standard Deviation 1.44 |
p-value: <0.001Chi-squared
Primary
Percentage of Actinic Keratosis (AK) Lesions Cleared
AK clearance after PDT and comparison between the sides The values in the data table represent the percentage of AK clearance on each side at 3, 6 and 12 months post intervention. At baseline: 290 on the CAL-PDT side and 284 on the conventional side.
Time frame: Change from baseline, 90 days, 6 months and 12 months after PDT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Calcipotriol Assisted MAL-PDT | Percentage of Actinic Keratosis (AK) Lesions Cleared | 3 months outcome | 92.1 percentage of lesions cleared |
| Calcipotriol Assisted MAL-PDT | Percentage of Actinic Keratosis (AK) Lesions Cleared | 6 months outcome | 92.1 percentage of lesions cleared |
| Calcipotriol Assisted MAL-PDT | Percentage of Actinic Keratosis (AK) Lesions Cleared | 12 months outcome | 90.7 percentage of lesions cleared |
| Conventional MAL-PDT | Percentage of Actinic Keratosis (AK) Lesions Cleared | 3 months outcome | 82 percentage of lesions cleared |
| Conventional MAL-PDT | Percentage of Actinic Keratosis (AK) Lesions Cleared | 6 months outcome | 81.7 percentage of lesions cleared |
| Conventional MAL-PDT | Percentage of Actinic Keratosis (AK) Lesions Cleared | 12 months outcome | 77.5 percentage of lesions cleared |
Secondary
Change From Baseline in Fluorescence Intensity of PPIX
Measurement of PPIX fluorescence on both sides of the scalp before and immediately after LED illumination PpIX fluorescence was measured in three different spot areas on the scalp before and immediately after PDT on each side. The measurements were taken noninvasively in the areas where PpIX fluorescence was more intense, with a handheld fluorescence photometer (USB 2000+ spectroscopy device; Ocean Optics, Dunedin, FL, U.S.A.). The photometer illuminates a circular skin area with a diameter of 1 cm with blue light (400-420 nm), matching the Soret band of PpIX at 405-420 nm. By measuring excitation wavelengths at 600- 700 nm, the corresponding red PpIX fluorescence intensity at 633 nm is detected. Measurements were taken in arbitrary units. The mean PpIX fluorescence value for each side was calculated before and after the treatment.
Time frame: Baseline and 10 minutes after illumination
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Calcipotriol Assisted MAL-PDT | Change From Baseline in Fluorescence Intensity of PPIX | 3422.85 arbitrary units | Standard Deviation 1775.19 |
| Conventional MAL-PDT | Change From Baseline in Fluorescence Intensity of PPIX | 2688.35 arbitrary units | Standard Deviation 1746.12 |
Comparison: Student's t-test or the Mann-Whitney test was used according to the assumption of normality of data for PpIX fluorescence intensityp-value: =0.048Wilcoxon (Mann-Whitney)
Secondary
Pain Scores Immediately Post Illumination
Measurement of pain during LED illumination and comparison between the sides with a visual analogue scale (VAS), considering 0 as absence of pain and 10 as the most severe pain. At baseline, before the illumination, there is an absence of pain, which means Score 0 (zero) for all participants before the procedure. Pain is reffered during and after the illumination and measured with the VAS scale, reported by each patient.
Time frame: immediately after intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Calcipotriol Assisted MAL-PDT | Pain Scores Immediately Post Illumination | 5.4 units on a scale | Standard Deviation 1.4 |
| Conventional MAL-PDT | Pain Scores Immediately Post Illumination | 4.0 units on a scale | Standard Deviation 0.69 |
p-value: =0.001Fisher Exact