1. British Journal of Dermatology. DOI: 10.1111/bjd.16473
A randomized split-scalp study comparing Calcipotriol assisted MAL-PDT with Conventional MAL-PDT for the treatment of Actinic Keratosis
Luis Torezan1, Beni Grinblat1, Merete Haedersdal2, Neusa Valente1, Cyro Festa-Neto1 and RM Szeimies3
1Department of Dermatology, Universidade de São Paulo, Hospital das Clinicas, São Paulo,
Brazil
2Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, Copenhagen,
Denmark
3Department of Dermatology and Allergology, Klinikum Vest GmbH, Recklinghausen, Germany
British Journal of Dermatology. DOI: /bjd.16473

2. Luis Torezan, Lead author

3. Introduction: What’s already known?
Topical Vitamin D pretreatment enhances methylaminolevulinate (MAL)-induced protoporphyrin IX (PpIX) in hairless mice.
Topical Vitamin D prior to aminolevulinic acid – photodynamic therapy (ALA-PDT) enhances treatment efficacy of non- melanoma skin cancers in mouse skin models

4. Objective
To compare the efficacy and safety of the combination of topical calcipotriol (CAL) before methylaminolevulinate (MAL)-PDT for AKs of the scalp versus conventional MAL-PDT in a randomized controlled-clinical trial.

5. Methods 20 patients (♂, mean age 73.15 yo) skin types I-II
symmetrically distributed AKs grades I/II on the scalp (at least 6 Aks)
Simple randomization method, by tossing a coin, was used to determine which side of the scalp was intervention or control.
All patients from Department of Dermatology Universidade de Sao Paulo Hospital das Clínicas, Sao Paulo, Brazil

6. Methods
One side: conventional MAL-PDT with previous gentle curettage ( 90 minutes incubation time)
Other side: pre treatment with Calcipotriol ointment (50mcg/g) for 15 days before conventional MAL-PDT
Illumination: LED 635 nm, total dose 37 J/cm² ( Aktilite®Photocure)
Follow-up: 1 and 3 months after, digital photographs
Biopsies taken before and 3 months after each side – 5 patients only

7. Study Design – Methods Randomized split-scalp – controlled and prospective
Primary objective: to compare the efficacy of CAL-assisted MAL-PDT with conventional MAL-PDT alone for AKs on the scalp. Investigators assessments of AK lesions were blinded
Secondary outcomes: mean PpIX fluorescence intensity and comparison between the sides and side effects such as pain and local skin reactions.
Intensity of pain: VAS scale, considering 0 as absence of pain and 10 as the most severe pain.
Local skin reactions (erythema, edema, pustules, crusts, erosions and ulcerations) assessed by a pre-defined scale as: 0 = no reaction, + mild, ++ moderate, +++ severe.

8. Results Lesions CAL PDT c PDT Total p-value1 n=290 n=284 n=574 n (%)
Distribution of AKs before and after PDT on Cal and conventional sides.
Lesions
CAL PDT
c PDT
Total
p-value1
n=290
n=284
n=574
n (%)
Complete response
267 (92.07)
233 (82.04)
500 (87.11)
<0.001
Uncured
23 (7.93)
51 (17.96)
74 (12.89)
Grade I
223 (76.90)
222 (78.17)
445 (77.53)
0.715
Grade II
67 (23.10)
62 (21.83)
129 (22.47)
n=223
n=222
n=445
0.055
207 (92.83)
194 (87.39)
401 (90.11)
Negative
16 (7.17)
28 (12.61)
44 (9.89)
n=67
n=62
n=129
60 (89.55)
39 (62.90)
99 (76.74)
7 (10.45)
23 (37.10)
30 (23.26)
1Pearson chi-square test.

9. Treatment PPIX (a.u.) cal PDT c PDT p-value1 n = 20 Before 0.048
Comparison between PpIX flourescence intensity of CAL-PDT and MAL-PDT sides before and after illumination
Treatment
PPIX (a.u.)
cal PDT
c PDT
p-value1
n = 20
Before
0.048
Mean (SD)
( )
( )
Median (min-max)
( )
( )
After
0.978
( )
( )
( )
( )
SD: standard deviation; min: minimum value; max: maximum value. 1Mann-Whitney test.

10. Distribution of side effects and pain score (VAS) on Conventional and CAL-PDT sides
C PDT
CAL_PDT
Total
P value
n = 20
n = 40
n (%)
Erythema +
7 (35.0)
3 (15.0)
10 (25.0)
0.0191 ++
13 (65.0)
11 (55.0)
24 (60.0)
+++
6 (30.0)
6 (15.0)
Edema
18 (90.0)
8 (40.0)
26 (65.0)
0.0021
2 (10.0)
13 (32.5)
1 (5.0)
1 (2.5)
Crusts
20 (100)
10 (50.0)
30 (7.0)
<0.0011
9 (45.0)
9 (22.5)
Pain (VAS) 3
5 (25.0)
0.0071 4
17 (42.5) 5
4 (20.0)
7 (17.5) 6 7
2 (5.0) 8
Mean (SD)
3.95 (0.69)
5.40 (1,43)
4.68 (1,33)
0.0012
Median (min-max)
4 (3-5)
5.5 (3-8)
4 (3-8)
SD: standard deviation; min: minimum value; max: maximum value. VAS: visual analog scale - Pain.
1Fisher exact test; 2 Mann-Whitney non-parametric test

11. Study Limitations /Discussion
Short follow-up of 3 months
Only 5 histopathological analyses before and after PDT
No placebo ointment was applied on the conventional side
Possible incorrect application of CAL by the patients, although strongly emphasized to apply the ointment on one half of the allocated side of the scalp.   

12. Comments/Discussion
Overall AK clearance of 92.07% vs % was achieved for CAL-PDT and MAL-PDT respectively (p<0.001)
Our results also corroborate the findings of previous animal model studies where CAL, as a preconditioning drug, enhanced the efficacy of tumor cell death after PDT
AKs grade II showed higher cure rates (89.55% vs 62.90%) on the vitamin D preconditioned side (p<0.001)
Our data may suggest a new combination treatment approach for “difficult-to-treat” AKs of the scalp since the combination of calcipotriol leads to a higher clearance of AKs in field cancerization compared to PDT alone. In thin AKs, but the difference in the clinical response compared to the non-pretreated AK is very small to induce significant effects.

13. Comments/Discussion
Overall AK clearance of 92.07% vs % was achieved for CAL-PDT and MAL-PDT respectively (p<0.001)
Our results also corroborate the findings of previous animal model studies where CAL, as a preconditioning drug, enhanced the efficacy of tumor cell death after PDT
AKs grade II showed higher cure rates (89.55% vs 62.90%) on the vitamin D preconditioned side (p<0.001)
Our data may suggest a new combination treatment approach for “difficult-to-treat” AKs of the scalp since the combination of calcipotriol leads to a higher clearance of AKs in field cancerization compared to PDT alone. In thin AKs, but the difference in the clinical response compared to the non-pretreated AK is very small to induce significant effects.
Mean PpIX measurement on CAL-assisted side compared to the conventional side (p 0.048)

14. More painful – probably to ↑↑ PpIX on the area pretreated with CAL
Mean PpIX measurement on CAL-assisted side compared to the conventional side (p 0.048)
Safe and effective
More painful – probably to ↑↑ PpIX on the area pretreated with CAL
No other concerns regarding side effects
Same impact on histology
Further and larger studies are needed

15. Conclusions
CAL-assisted PDT proved to be safe and more effective than conventional MAL-PDT for the treatment of AKs on the scalp. CAL pretreatment increased PpIX accumulation within the skin and may have enhanced the efficacy in this first human trial. As this is the first CAL-assisted PDT study in human skin, further and larger trials are needed to corroborate our findings.

16. What does this study add?
In human skin, calcipotriol assisted MAL-PDT proved to be superior and well-tolerated to MAL-PDT alone.
Topical preconditioning of Actinic Keratosis (AK) with calcipotriol enhanced MAL- induced PpIX formation compared to non-pretreated side.

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