Long-term Outcome of Low-concentration Hexyl-5-aminolaevulinate Daylight Photodynamic Therapy for Treatment of Actinic Keratoses

Ac aDV Ac aDV Ad ances in de ma ology and ene eology Ac a De ma o-Vene eologica SHORT COMMUNICATION doi: 10.2340/00015555-2484 Jou nal Compila ion © 2017 Ac a De ma o-Vene eologica. This is an open access a icle unde he CC BY-NC license. www.medicaljou nals.se/ac a Ac a De m Vene eol 2017; 97: 120–121 120 Dayligh pho odynamic he apy (DL-PDT), using sho - chained 5-aminolae ulina e (5-ALA) es e me hylamino- lae ulina e (MAL), is an e ec i e and well- ole a ed ea men o ac inic ke a oses (AK) (1). Recen ly, he e has been in e es in he no el long-chained 5-ALA es e hexylaminolae ulina e (HAL), which has be e skin pene a ion and can hus be used a low concen a ions (2–4). This could be o economic alue and educe side-e ec s (5). We ha e epo ed p e iously ha e y low concen a ions o HAL can be used wi h dayligh ac i a ion (6). The cu en pape epo s he long- e m 12-mon h ou come. METHODS The me hods a e desc ibed in de ail elsewhe e (6). Volun ee pa ien s wi h symme ical ac inic damage in he head a ea we e e- c ui ed and ea ed in June 2014. AKs we e pho og aphed, coun ed and ma ked on a plas ic shee , and 2 symme ical equally g aded (6) AKs, one on each ea men side, we e biopsied bila e ally be o e ea men . A chemical sunsc een (P20®, SPF 20 Riemann & Co. A/S, Hille oed, Denma k) was applied o 15 min, and he ea men a eas we e subsequen ly cu e - aged. Pa ien s we e andomized o e- cei e DL-PDT wi h 0.2% HAL (Hex ix® powde , Pho ocu e ASA, Oslo, No way in Unguen um M, Allmi al, Mad id, Spain) on one side o he ace o scalp and 16% MAL (Me ix, Galde ma, Pa is, F ance) on he o he , bo h applied as a 0.025 mm2 hick laye ( ea men a ea mm2 * 0.25 mg/mm2). Illumina ion was pe o med o 2 h ou doo s. Follow-up isi s, including he mapping o he esidual lesions and his ological sampling, was conduc ed by he blinded in es iga o (MG). The his o- logy (HE s aining and p53 exp ession in a e age pe cen age o he 3 high powe ields) o he samples was in e p e ed by a blinded pa hologis (TTT). Wilcoxon signed- ank pai ed es was used o s a is ical analysis. RESULTS O he 14 pa ien s who comple ed he pilo ial, 13 we e ollowed up o 12 mon hs. One pa ien died be o e he 12-mon h ollow-up due o easons un ela ed o he s udy. No esidual lesions we e ea ed be ween he 3- and 12-mon h ollow-ups. Bo h ea men s we e nea ly painless ( isual analogue scale (VAS) ≤ 1). HAL caused milde ad e se eac ions, as assessed a 1 week (6). A 12 mon hs HAL DL-PDT esul ed in simila sus- ained lesion clea ance compa ed wi h MAL (Fig. 1 and Table I). The mean lesion clea ance pe pa ien was 67% wi h HAL and 66% wi h MAL (p = 1.00). HAL was as e ec i e as MAL in he ea men o g ade I AKs, bu a end o lowe clea ance o g ade II–III AKs was seen (Fig. 2 and Table I). One pa ien was excluded om he his ological analysis because one biopsied lesion clinically aken as an AK appea ed his ologically o be sebo hoeic de ma i is. His ological clea ance was equal o bo h pho osensi ize s (Table I). A 12 mon hs, 42% o he HAL- ea ed and 50% o he MAL- ea ed biopsied lesions we e comple ely his ologically clea ed (p = 0.688). Compa ed wi h baseline, he mean exp es- sion o p53 was educed by 20% in he HAL g oup and by 51% in he MAL g oup (p = 0.123). Long- e m Ou come o Low-concen a ion Hexyl-5-aminolae ulina e Dayligh Pho odynamic The apy o T ea men o Ac inic Ke a oses Noo a NEITTAANMÄKI 1,2 , Toni T. KARPPINEN 3 , Taneli T. TANI 4 , E na SNELLMAN 3 and Ma i GRÖNROOS 2 Depa men s o De ma ology and Alle gology, 1 Helsinki Uni e si y Cen al Hospi al, FIN-00029 Helsinki and 2 Päijä -Häme Social and Heal h Ca e G oup, Lah i, 3 Depa men o De ma ology, Tampe e Uni e si y and Tampe e Uni e si y Hospi al, Tampe e, and 4 Depa men o Pa hology, Päijä -Häme Social and Heal h Ca e G oup, Lah i, Finland. E-mail: [email p o ec ed] Accep ed Jun 1, 2016; Epub ahead o p in Jun 15, 2016 Fig. 1. Comple e clea ance o ac inic ke a oses a e dayligh pho odynamic he apy wi h hexylaminolae ulina e (HAL) (le side, a and c) and wi h me hylaminolae ulina e (MAL) ( igh side, b and d). (a) and (b) be o e ea men ; (c) and (d) 12 mon hs a e ea men . Ac aDV Ac aDV Ad ances in de ma ology and ene eology Ac a De ma o-Vene eologica 121Sho communica ion Ac a De m Vene eol 2017 DISCUSSION P e iously, HAL has been s udied a e y low 0.1% con- cen a ions o he p e en ion o cu aneous squamous ca cinoma in mice (7). HAL-induced p o opo phy in IX (PpIX) luo escence has been epo ed in se e al s udies and i has been shown ha HAL has g ea po en ial when used a low concen a ions (8–11). We epo ed a 3-mon h mean pe -pa ien lesion clea ance o 73.4% wi h HAL and 77.8% wi h MAL (6), which is in conco dance wi h p e ious DL-PDT s udies (1). Long- e m clea ance is a- ely epo ed in DL-PDT s udies. Recen ly, 62% and 87% mean pe -pa ien lesion clea ance was epo ed o MAL and amino-5-laeu ulina e nanoemulsion (BF-200 ALA) (12). In ou cu en s udy a 12 mon hs he clea ances we e 67% o HAL and 66% o MAL, which suppo s he p e- ious 12-mon h da a wi h MAL. Ou esul s show simila e icacies o HAL and MAL in he long- e m ollow-up. A limi a ion o ou pilo s udy was he small sample size. As lowe clea ance was seen wi h hicke g ade II–III lesions, low-concen a ion HAL should only be used o hin AKs. The ac ha p53 exp ession was less educed in he HAL g oup may indica e poo e e e sal in he ca - cinogene ic p ocess. Howe e , o e a long pe iod, he e was also sus ained clea ance o AKs in he HAL g oup. Ou esul s show ha low concen a ions o HAL can be used in he ea men o hin AKs and his clea ance was main ained in a long- e m ollow-up. The use o HAL a e y low doses could lead o signi ican educ- ions in ea men cos s. ACKNOWLEDGEMENTS The s udy has been suppo ed by he Founda ion o Clinical Chemis y Resea ch. NN has ecei ed a el g an s om Bio on- e a and Galde ma and was speake hono a ia o Bio on e a and Desi in Pha ma. The o he au ho s decla e no con lic o in e es . Regis a ion no.: R14016M, E hics Commi ee Tampe e Uni e si y Dis ic . Clinical ials.go egis a ion no.: NCT02149342. REFERENCES 1. Wiegell SR, Wul HC, Szeimies RM, Basse -Seguin N, Bisson- ne e R, Ge i sen MJ, e al. Dayligh pho odynamic he apy o ac inic ke a osis:an in e na ional consensus: In e na ional Socie y o Pho odynamic The apy in De ma ology. J Eu Acad De ma ol Vene eol 2012; 26: 673–679. 2. 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Compa ison o ALA- and ALA hexyl-es e - induced PpIX dep h dis ibu ion in human skin ca cinoma. J Pho ochem Pho obiol B 2008; 93: 140–148. 11. Juzeniene A, Juzenas P, Ma LW, Iani V, Moan J. Topical appli- ca ion o 5-aminolae ulinic acid, me hyl 5-aminolae ulina e and hexyl 5-aminolae ulina e on no mal human skin. B J De ma ol 2006; 155: 791–799. 12. Nei aanmäki-Pe u N, G ön oos M, Tani T, Snellman E. Long- e m ou come o dayligh pho odynamic he apy wi h 5-ami- nolae ulina e nanoemulsion and me hyl-5-aminolae ulina e o ac inic ke a oses. Ac a De m Vene eol 2016; 96: 712–713. Table I. Baseline cha ac e is ics, clinical and his ological clea ance a es a 12 mon hs HAL MAL p- alues Clinical Baseline To al numbe o lesions 95 88 0.695 G ade I lesions 71 67 0.711 G ade II–III lesions 24 21 0.625 Lesions/pa ien , mean ( ange) 7.3 (3–14) 6.8 (3–10) 12 mon hs Comple e esponse all (mean) % pe pa ien ) 66.5 65.9 1.000 G ade I 76.2 63.1 0.285 G ade II–III 44.4 78.7 0.156 New lesions 3 1 0.625 His ological Baseline biopsied lesions 12 12 G ade I 2 4 0.625 G ade II–III 10 80.625 p53, mean (%) 37.6 37.4 0.791 12 mon hs Comple e esponse, % 41.6 50 0.688 Mean educ ion in p53 exp ession, % 20 51 0.123 HAL: hexylaminolae ulina e; MAL: me hylaminolae ulina e. Fig. 2. Mean pe pa ien (hal - ace) lesion clea ance (%) a 12 mon hs. HAL: hexylaminolae ulina e; MAL: me hylaminolae ulina e; AK: ac inic ke a oses. 80 60 40 20 0 Comple e clea ance all g ades g ade I AKs and g ade II–III AKs HAL MAL