[Potassium hydroxide 5 % solution in actinic keratosis : A novel therapeutic approach in the lesion-directed treatment]. / Kaliumhydroxid-5 %-Lösung bei aktinischer Keratose : Ein neuer Therapieansatz zur läsionsgerichteten Behandlung.

BACKGROUND: Actinic keratosis (AK) is an epithelial carcinoma in situ of the skin. There is a need for early treatment due to the risk of malignant transformation. In addition to being effective, the initial therapy in particular should be well tolerated and user-friendly. Potassium hydroxide (KOH) solution is already established as keratolytic treatment option for hyperkeratotic skin diseases such as mollusca contagiosa. MATERIALS AND METHODS: A prospective single-arm, multicentre medical device study (Treatment of AK with KOH, TAKKOH) was conducted to investigate the efficacy and safety of KOH 5% solution for the treatment of mild to moderate AK. Patients applied KOH solution twice daily for 14 days with a subsequent off-treatment phase of 14 days (≙ one treatment cycle) for a maximum of three treatment cycles or at least until treatment success was achieved. Treatment success, defined as complete remission (CR) of all AK lesions of a patient, was the primary objective. Secondary objectives included the evaluation of partial remission (PR), the number of AK lesions in remission, efficacy assessment by investigators and patients with a 6­point grading system and several safety parameters. RESULT: In all, 73 patients were enrolled in the study. CR was achieved in 54.9% of patients, whereas PR was observed in 64.8% with a 69.9% reduction in lesion numbers. With respect to safety, 46.6% of the patients experienced adverse events. Most of these events (82.6%) were adverse reactions comprising exclusively short-lived and mild local skin reactions. CONCLUSIONS: The study provides an indication of the efficacy and safety of KOH 5% solution for the lesion-directed topical therapy of AK.

A randomized, multinational, noninferiority, phase III trial to evaluate the safety and efficacy of BF-200 aminolaevulinic acid gel vs. methyl aminolaevulinate cream in the treatment of nonaggressive basal cell carcinoma with photodynamic therapy.

BACKGROUND: Basal cell carcinoma (BCC) represents the most common nonmelanoma skin cancer worldwide, affecting mainly adult, fair-skinned individuals. The World Health Organization distinguishes aggressive and nonaggressive forms, of which prototypical variants of the latter are primary nodular and superficial BCC. OBJECTIVES: To demonstrate noninferiority of BF-200 ALA (a nanoemulsion gel containing 5-aminolaevulinic acid) compared with MAL (a cream containing methyl aminolaevulinate) in the treatment of nonaggressive BCC with photodynamic therapy (PDT). Noninferiority of the primary efficacy variable (overall patient complete response 12 weeks after last PDT) would be declared if the mean response for BF-200 ALA was no worse than that for MAL, within a statistical margin of Δ = -15%. METHODS: The study was a randomized, phase III trial performed in Germany and the U.K. with ongoing 5-year follow-up. Of 281 randomized patients, 138 were treated with BF-200 ALA and 143 with MAL. Patients received two PDT sessions 1 week apart. Remaining lesions 12 weeks after the second PDT were retreated. Illumination was performed with a red light source (635 nm, 37 J cm-2 ). The results shown include clinical end points and patients' reassessment 12 months after the last PDT. The study was registered with EudraCT (number 2013-003241-42). RESULTS: Of the BF-200 ALA-treated patients, 93·4% were complete responders compared with 91·8% in the MAL group. The difference of means was 1·6, with a one-sided 97·5% confidence interval of -6·5, establishing noninferiority (P < 0·0001). The results for secondary efficacy parameters were in line with the primary outcome. Recurrence rates 12 months after the last treatment were ≤ 10%. CONCLUSIONS: Treatment of nonaggressive BCC with BF-200 ALA-PDT is highly effective and well tolerated with proven noninferiority to MAL-PDT. It demonstrates low recurrence rates after 1 year of follow-up.

Long-term (6 and 12 months) follow-up of two prospective, randomized, controlled phase III trials of photodynamic therapy with BF-200 ALA and methyl aminolaevulinate for the treatment of actinic keratosis.

BACKGROUND: Two phase III trials of photodynamic therapy (PDT) with BF-200 ALA, a recently approved nanoemulsion formulation of 5-aminolaevulinic acid (ALA) demonstrated high clearance rates in mild-to-moderate actinic keratosis (AK). The comparison to a registered methyl aminolaevulinate (MAL) cream demonstrated significantly superior total patient clearance rates. OBJECTIVES: To evaluate long-term efficacy and safety of PDT for AK 6 and 12 months after the last PDT with BF-200 ALA, MAL or placebo. METHODS: The follow-up phase (FUP) was performed with patients of two phase III studies. Both studies compared BF-200 ALA with placebo, one of the studies additionally with MAL. Overall recurrence rates and various subgroups (light source, lesion severity, lesion location, complete responders after first PDT) were assessed 6 and 12 months after the last PDT. RESULTS: Recurrence rates were similar for BF-200 ALA and MAL, with a tendency to lower recurrence rates for BF-200 ALA. The proportion of patients who were fully cleared during PDT and remained completely clear for at least 12 months after PDT were 47% for BF-200 ALA (both studies) and 36% for MAL treatment. The subgroup that was illuminated with narrow wavelength LED lamps reached 69% and 53% for BF-200 ALA (both studies, respectively) and 41% for MAL. No safety concerns were reported. CONCLUSIONS: The FUP data confirmed the high efficacy and safety of PDT with BF-200 ALA. The slightly lower recurrence rates after BF-200 ALA treatment compared with MAL treatment enhanced the better treatment outcome due to the significantly superior efficacy.

Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: results of a multicentre, randomized, observer-blind phase III study in comparison with a registered methyl-5-aminolaevulinate cream and placebo.

BACKGROUND: Photodynamic therapy (PDT) with 5-aminolaevulinic acid (ALA) or its methylester [methyl-5-aminolaevulinate (MAL) or 5-amino-4-oxopentanoate] was recently ranked as first-line therapy for the treatment of actinic keratosis (AK) and is an accepted therapeutic option for the treatment of neoplastic skin diseases. BF-200 ALA (Biofrontera Bioscience GmbH, Leverkusen, Germany) is a gel formulation of ALA with nanoemulsion for the treatment of AK which overcomes previous problems of ALA instability and improves skin penetration. OBJECTIVES: To evaluate the efficacy and safety of PDT of AKs with BF-200 ALA in comparison with a registered MAL cream and with placebo. METHODS: The study was performed as a randomized, multicentre, observer-blind, placebo-controlled, interindividual trial with BF-200 ALA, a registered MAL cream and placebo in a ratio of 3:3:1. Six hundred patients, each with four to eight mild to moderate AK lesions on the face and/or the bald scalp, were enrolled in 26 study centres in Germany, Austria and Switzerland. Patients received one PDT. If residual lesions remained at 3months after treatment, PDT was repeated. RESULTS: PDT with BF-200 ALA was superior to placebo PDT with respect to patient complete clearance rate (78·2% vs. 17·1%; P<0·0001) and lesion complete clearance rate (90·4% vs. 37·1%) at 3months after the last PDT. Moreover, superiority was demonstrated over the MAL cream regarding the primary endpoint patient complete clearance (78·2% vs. 64·2%; P<0·05). Significant differences in the patient and lesion complete clearance rates and severity of treatment-related adverse events were observed for the narrow- and broad-spectrum light sources. CONCLUSIONS: BF-200 ALA is a very effective, well-tolerated new formulation for AK treatment with PDT and is superior to a registered MAL medication. Efficacies and adverse events vary greatly with the different light sources used.

Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: results of a prospective, randomized, double-blind, placebo-controlled phase III study.

BACKGROUND: Photodynamic therapy (PDT) with 5-aminolaevulinic acid (ALA) provides a therapeutic option for the treatment of actinic keratosis (AK). Different strategies are applied to overcome the chemical instability of ALA in solution and to improve skin penetration. A new stable nanoemulsion-based ALA formulation, BF-200 ALA, is currently in clinical development for PDT of AK. OBJECTIVES: To evaluate the efficacy and safety of PDT of AK with BF-200 ALA. METHODS: The study was performed as a randomized, multicentre, double-blind, placebo-controlled, interindividual, two-armed trial with BF-200 ALA and placebo. A total of 122 patients with four to eight mild to moderate AK lesions on the face and/or the bald scalp were included in eight German study centres. The efficacy of BF-200 ALA after one and two PDT treatments was evaluated. BF-200 ALA was used in combination with two different light sources under illumination conditions defined by European competent authorities. RESULTS: PDT with BF-200 ALA was superior to placebo PDT with respect to patient complete clearance rate (per-protocol group: 64% vs. 11%; P < 0.0001) and lesion complete clearance rate (per-protocol group: 81% vs. 22%) after the last PDT treatment. Statistically significant differences in the patient and lesion complete clearance rates and adverse effect profiles were observed for the two light sources, Aktilite CL128 and PhotoDyn 750, at both time points of assessment. The patient and lesion complete clearance rates after illumination with the Aktilite CL128 were 96% and 99%, respectively. CONCLUSIONS: BF-200 ALA is a very effective new formulation for the treatment of AK with PDT. Marked differences between the efficacies and adverse effects were observed for the different light sources used. Thus, PDT efficacy is dependent both on the drug and on the characteristics of the light source and the illumination conditions used.

Adjuvant low-dose interferon {alpha}2a with or without dacarbazine compared with surgery alone: a prospective-randomized phase III DeCOG trial in melanoma patients with regional lymph node metastasis.

BACKGROUND: More than half of patients with melanoma that has spread to regional lymph nodes develop recurrent disease within the first 3 years after surgery. The aim of the study was to improve disease-free survival (DFS) and overall survival (OS) with interferon (IFN) alpha2a with or without dacarbazine (DTIC) compared with observation alone. PATIENTS AND METHODS: A total of 444 patients from 42 centers of the German Dermatologic Cooperative Oncology Group who had received a complete lymph node dissection for pathologically proven regional node involvement were randomized to receive either 3 MU s.c. of IFNalpha2a three times a week for 2 years (Arm A) or combined treatment with same doses of IFNalpha2a plus DTIC 850 mg/m(2) every 4-8 weeks for 2 years (Arm B) or to observation alone (Arm C). Treatment was discontinued at first sign of relapse. RESULTS: A total of 441 patients were eligible for intention-to-treat analysis. Kaplan-Meier 4-year OS rate of those who had received IFNalpha2a was 59%. For those with surgery alone, survival was 42% (A versus C, P = 0.0045). No improvement of survival was found for the combined treatment Arm B with 45% survival rate (B versus C, P = 0.76). Similarly, DFS rates showed significant benefit for Arm A, and not for Arm B. Multivariate Cox model confirmed that Arm A has an impact on OS (P = 0.005) but not Arm B (P = 0.34). CONCLUSIONS: 3 MU interferon alpha2a given s.c. three times a week for 2 years significantly improved OS and DFS in patients with melanoma that had spread to the regional lymph nodes. Interestingly, the addition of DTIC reversed the beneficial effect of adjuvant interferon alpha2a therapy.

[Skin tumors in organ-transplant recipients]. / Hauttumoren transplantierter Patienten.

Skin cancers are a significant medical problem for organ-transplant recipients. Squamous cell carcinoma and basal cell carcinoma are most common tumors. An increasing incidence of melanoma, Kaposi sarcoma, Merkel cell carcinoma, as well as uncommon skin malignancies, is also seen. Predisposing factors include cumulative sun exposure, cumulative immunosuppression, age, gender, skin type, virus detection and genetic alterations. Skin tumors grow rapidly and their number continues to increase in the years following transplantation. Large numbers of tumors, aggressive courses and appearance in young patients are other characteristics of these skin tumors. More general awareness of the need for preventive measures and regular dermatological examinations is desirable. In addition standardized registries are needed to assure the comparability of data, to better correlate immunosuppression with skin tumors and to plan therapeutic studies.

Phase II trial of intralesional therapy with interleukin-2 in soft-tissue melanoma metastases.

The objective of the present study was to validate the use of intralesional injection of interleukin-2 (IL-2) in patients with skin and soft-tissue melanoma metastases. A total of 24 patients with AJCC stage III or IV melanoma and single or multiple skin and soft-tissue metastases were included. Interleukin-2 injections were administered intralesionally into the total number of cutaneous and soft-tissue metastases accessible from the skin, 2-3 times weekly, over 1-57 weeks. Single doses varied from 0.6 to 6 x 10(6) IU, depending on lesion size. The clinical response was monitored by sonography and confirmed by histopathology; response evaluation was confined to the intralesionally treated tumours. Complete response (CR) of the treated metastases was achieved in 15 patients (62.5%), the longest remission lasting 38 months to date. In five patients, partial response (PR) was achieved (21%) and in another three patients, progressive disease was observed (one patient not assessable). A total of 245 metastases were treated with CR in 209 (85%), and PR in 21 (6%). The therapy was generally well tolerated; the observed adverse events were mainly of grade 1-2 severity. Immunohistochemical studies showed the tumour cells undergoing apoptosis and revealed a mixed character of the inflammatory infiltrate. The unusual high CR rate in metastatic melanoma of 62.5% and the limited toxicity suggest that treatment of skin and soft-tissue melanoma metastases with intralesional injection of IL-2 may be a safe and effective alternative to conventional therapies. The optimal dosage and duration of this therapy still remain to be defined in larger prospective multicentre trials.

Intralesional rituximab for cutaneous B-cell lymphoma.

Rituximab, a chimeric anti-CD20 monoclonal antibody, has been approved for systemic treatment of relapsed or refractory CD20-positive B-cell non-Hodgkin's lymphoma. As cutaneous B-cell lymphoma (CBCL) also expresses the CD20 molecule, three patients with histologically and immunohistochemically confirmed CBCL without systemic involvement were treated with low-dose intralesional rituximab in a pilot study. Single doses applied ranged from 10 to 30 mg per lesion, according to lesion extent, with a cumulative dose of up to 350 mg. Injections were given two or three times weekly for 3-5 weeks, with a second cycle after 6 weeks in one patient with incomplete remission. Complete and lasting remission was achieved in each patient; this has persisted for up to more than 1 year. The observed adverse events were of grade 1 severity. Results suggest that intralesional rituximab may be a safe and effective new therapy modality for CBCL.