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