CLINICAL REPORT
617 ActaDV ActaDV Advances in dermatology and venereology Acta Dermato-Venereologica
Pretreatment with 5-Fluorouracil Cream Enhances the Efficacy of Daylight-mediated Photodynamic Therapy for Actinic Keratosis
Christoffer V . NISSEN 1 , Ida M . HEERFORDT 1 , Stine R . WIEGELL 1 , Carsten S . MIKKELSEN 2 and Hans Christian WULF 1
1
Department of Dermatology , Bispebjerg Hospital , University of Copenhagen , Bispebjerg Copenhagen , and 2 Clinic of Dermatology , Broenderslev , Denmark
The efficacy of photodynamic therapy ( PDT ) with methyl aminolevulinate is reduced when treating actinic keratosis ( AK ) on the extremities in comparison with the face and scalp . Studies indicate that PDT efficacy can be improved by combining PDT with other treatment modalities . This randomized intra-individual study investigated whether pretreatment with topical 5 % 5-fluorouracil ( 5-FU ) enhanced the treatment efficacy of daylight-mediated PDT in 24 patients with AKs on the hands . One hand of each patient was given 7 days of pretreatment with 5-FU twice daily before daylight-PDT , whereas the other hand was treated with daylight-PDT alone . At 3-month follow-up the overall lesion response rate was significantly higher for the combination of 5-FU and daylight-PDT ( 62.7 %) than for daylight-PDT alone ( 51.8 %) ( p = 0.001 ). Furthermore , pain and erythema in relation to treatment were similar in the 2 groups ( p = 1.0 and p = 0.2 , respectively ). Combination therapy is a safe and effective method to improve daylight-PDT for acral AKs .
Key words : 5-fluorouracil ; actinic keratosis ; daylight-PDT ; photodynamic therapy ; pretreatment .
Accepted Jan 12 , 2017 ; Epub ahead of print Jan 17 , 2017 Acta Derm Venereol 2017 ; 97 : 617 – 621 .
Corr : Christoffer V . Nissen , Department of Dermatology D92 , Bispebjerg Hospital , University of Copenhagen , Bispebjerg Bakke 23 , DK-2400 Copenhagen NV , Denmark . E-mail : christoffer . valdemar . nissen @ regionh . dk
Photodynamic therapy ( PDT ) is an established and effective treatment modality for actinic keratosis ( AK ) ( 1 ). In PDT , a topical prodrug is enzymatically converted into the photosensitive molecule protoporphyrin IX ( PpIX ) within epidermal cells . Subsequent activation of PpIX with light of appropriate wavelengths leads to necrosis and apoptosis of the affected cells ( 2 , 3 ).
PDT efficacy is high when treating AKs on the face and scalp ( 4 ), but studies report efficacy rates to be approximately 20 % lower on the extremities ( 5 – 8 ). This discrepancy in response rates was believed to be caused by insufficient PpIX accumulation in acral skin regions due to lower skin temperatures and a limited number of pilosebaceous glands ( 5 , 8 ). However , in a recent study we found no improvement in PDT efficacy for AK on the hands after successfully increasing PpIX accumulation markedly ( 9 ). Consequently , different strategies are needed to improve PDT treatment of AKs on the extremities . A pro- mising new approach is to use PDT in combination with other treatment modalities ( 10 ). Combination therapy has the advantage of attacking a disease through different mechanisms of action , which could produce an additive effect that exceeds the results achieved via monotherapy ( 11 ). Research is sparse , but the topical therapeutics imiquimod ( 12 , 13 ), diclofenac ( 14 ), ingenol mebutate ( 15 ) and 5-fluorouracil ( 5-FU ) ( 16 – 18 ) have all been combined with PDT in small studies or case reports with promising results .
For combination therapy with PDT to be attractive to both patients and physicians the treatment duration should be short , the economic burden must be low , the number of consultations should be kept to a minimum and adverse events should not exceed those of monotherapy . This makes short-term topical treatment with 5-FU an obvious candidate to combine with PDT . Consequently , we investigated whether sequential treatment with 5 % 5-FU cream for 7 days could improve the efficacy of daylight-PDT with methyl aminolevulinate ( MAL ) when treating AKs on the hands . Furthermore , we assessed adverse events , daylight illuminance , 5-FU consumption and PpIX accumulation in relation to treatment .
METHODS Patients
Patients older than 18 years with multiple AKs on the dorsal side of both hands were recruited for this randomized controlled study with open evaluation . Exclusion criteria were : porphyrias , known allergy to the study medication , organ transplant recipients , concurrent treatment with oral immunosuppressive drugs , pregnancy , and lactation . All patients had chronic photo-damaged skin and had previously been treated with a wide range of treatment modalities for AKs on different body sites . However , no patients had been treated on the hands within the 3 months prior to inclusion .
The study was conducted from August 2015 to January 2016 at 2 dermatology clinics in Denmark and was approved by the Danish Health and Medicines Authority ( EudraCT 2015-003003-29 ) and the ethics committee of Region Hovedstaden ( H-15009690 ). Signed informed consent was obtained from all patients prior to study start .
Study procedures
AKs on the dorsal side of both hands were mapped on a template and graded according to Olsen et al . ( 19 ). Subsequently , each hand was randomly allocated to receive either daylight-mediated PDT ( D-PDT ) as monotherapy or sequential treatment with 5-FU and daylight-mediated PDT ( 5FU-D-PDT ). The randomization
This is an open access article under the CC BY-NC license . www . medicaljournals . se / acta Journal Compilation © 2017 Acta Dermato-Venereologica . doi : 10.2340 / 00015555-2612 Acta Derm Venereol 2017 ; 97 : 617 – 621