Effective treatment of actinic keratosis on the hands with red light photodynamic therapy using BF-200 ALA.

BACKGROUND: Acral actinic keratosis (AK) lesions are considered difficult to treat, and published data for photodynamic therapy (PDT) on these lesions is limited. Thus, we evaluated sustained efficacy, safety, and satisfaction after PDT for AK on the hands. METHODS: We analysed subgroup data for treatment on the hands from a randomised, double-blind, intra-individual phase III study. All participants previously underwent up to two field-directed red light PDTs with 10% 5-aminolevulinic acid nanoemulsion gel (BF-200 ALA). Assessments included pain during PDT, clearance and recurrence rates, and satisfaction. RESULTS: 24 participants treated on the hands were included; 21 participants were analysed. Complete clearance rates with BF-200 ALA were 90.9% (lesion-based) and 76.2% (per participant's side), both markedly higher than with vehicle. The lesion recurrence rate with BF-200 ALA was 29.0%. Adverse events reflected the mode of action. Mean pain intensities were 4.8 ± 3.8 (BF-200 ALA) and 0.8 ± 2.1 (vehicle) on an 11-point numeric rating scale. Most participants (81.0%) rated their satisfaction with BF-200 ALA as very good or good. CONCLUSION: This subgroup analysis indicates that PDT with BF-200 ALA provides a suitable treatment for AK lesions on the hands.

5-ALA loaded self-adhesive patch-PDT is effective and safe in the treatment of actinic keratoses on hands and arms.

Photodynamic therapy (PDT) with 5-aminolevulinic acid hydrochloride (ALA) is an established method for the management of AK. PD P 506 A (brand name Alacare®) is an approved medicinal product for the treatment of AK located on scalp and face. It is a self-adhesive, light-proof patch loaded with 5-ALA HCl and was developed for easy handling. AK located on arms, hands or trunk do not respond as well to ALA-PDT as AK lesions on the head do. It has been reported that occlusion during ALA incubation can improve clinical outcome after ALA-PDT for AK on hands and arms. We present the results of a first explorative pilot study involving 20 participants with a total of 145 treated (122 evaluable) AK lesions. The trial investigated the conduct of two ALA-PDTs within 1-2 weeks and involved all severity grades of AK. The model-based percentage of complete clearance on lesion-basis was estimated being 78.0% (95%-CI: [64.6%, 87.3%]), and the by-participant calculation (patient-based clearance) led to similar results (78.7% with a 95%-CI of [67.0%, 90.3%]). The treatment was well tolerated. Local reactions during ALA patch incubation were rare whereas nearly all patients showed the expected reactions during or after the illumination, primarily erythema and pain. The study results indicate that two PD P 506 A-PDT sessions 1-2 weeks apart are an efficacious treatment for AK on hands and arms. Especially mild but also moderate lesions responded very well to PDT treatment involving ALA incubation under occlusion.

No room for pain: A prospective study showing effective and nearly pain-free treatment of actinic keratosis with simulated daylight photodynamic therapy (SDL-PDT) using the IndoorLux® System in combination with BF-200 ALA (Ameluz®).

BACKGROUND: Photodynamic therapy (PDT) with natural daylight is effective and less painful than conventional PDT when treating actinic keratosis (AK), however its weather dependency is restrictive. This prospective open-label observational single-arm study examined efficacy and safety of simulated daylight (SDL)-PDT using the IndoorLux® system in combination with 5-aminolevulinic acid gel (BF-200 ALA). METHODS: 12 patients with mild/moderate AK on the face or scalp received two SDL-PDTs. BF-200 ALA was applied prior to a 2 h illumination with the IndoorLux® System. Patients evaluated pain during and after SDL-PDT on visual analogue scales (VAS). Primary endpoint was lesion count reduction three months after the second SDL-PDT. Secondary endpoint was pain during and after illumination. RESULTS: Median individual clearance rate was 83.75% (66.7-100.0%); 33.3% of the patients and 84.9% of the lesions were completely cleared. Median size of the remaining partially cleared lesions decreased by 42.9%. The first SDL-PDT was pain-free for 7 patients (58.3%, VAS=0). Median VAS during and after the first treatment was 0 (0.0-0.3). For the second SDL-PDT, median VAS was 0.1 (0.0-5.5, during) and 0 (0.0-4.5, after). Both SDL-PDTs were pain-free for 6 patients. CONCLUSION: SDL-PDT was effective and nearly pain-free, emphasizing its advantages and potential for common practice.

Red light photodynamic therapy with BF-200 ALA showed superior efficacy in the treatment of actinic keratosis on the extremities, trunk, and neck in a vehicle-controlled phase III study.

BACKGROUND: Actinic keratoses (AK) may occur in all sun-exposed skin areas. Those occurring outside the head area are generally more resistant to treatment than those on the face. OBJECTIVE: To determine efficacy and safety of BF-200 ALA versus vehicle in the treatment of mild-to-severe AK located on extremities, trunk, and neck with red light photodynamic therapy (PDT). METHODS: This phase III study had an intra-individual design with 50 patients in 6 centers in Germany. Each patient received a maximum of 2 field-directed PDTs. Clinical end points and 1-year follow-up results were recorded. RESULTS: BF-200 ALA was superior to the vehicle with respect to total lesion clearance rates (86.0% vs 32.9%; P < .0001) and patient complete clearance per patient's side (67.3% vs 12.2%, P < .0001). One-year overall lesion recurrence rate was 14.1% versus 27.4% (BF-200 ALA vs vehicle; P = .0068). Patients were more satisfied by the cosmetic outcome of BF-200 ALA/PDT than the vehicle/PDT. Adverse events were consistent with the known safety profile of BF-200 ALA/PDT. LIMITATIONS: Small number of severe lesions; limited sample size; unbalanced but representative distribution of AK. CONCLUSION: BF-200 ALA showed significantly higher AK clearance rates on extremities, trunk, and neck than the vehicle and was well tolerated.

Long-term use of fumaric acid esters for the treatment of psoriasis in daily practice.

BACKGROUND: Fumaric acid ester (FAE) is the most commonly prescribed first-line systemic therapy for the treatment of psoriasis in Germany. Although developed in the 1990s, only limited long-term data are available. METHODS: Data of 200 adult psoriatic patients from 10 study centers were collected in a noninterventional, multicenter, retrospective analysis. The inclusion criteria was treatment with FAE in 2015. RESULTS: Eighty-two percent of the patients were naive to systemic treatment. Ten percent of all patients had FAE-treatment for 10 years or longer with an average drug survival of 4.32 years. The maintenance dose was ranging from 1-4 120 mg tablets for 87.5% of the patients. In our population, 14% of the patients stopped therapy during the first six month mainly due to gastro-intestinal side effects. No serious side effects were reported. Seventy-eight percent of the patients responded to FAE therapy with improvement of their psoriasis to mild (61%) or clear (17%). The PASI 75 response was achieved in 44% of the patient during long-term treatment without remarkable differences between moderate or severe plaque psoriasis. CONCLUSION: Our study confirms FAE therapy as a long-term, first-line treatment for moderate-to-severe plaque psoriasis.

Prognostic significance of an 11-gene RNA assay in archival tissue of cutaneous melanoma stage I-III patients.

PURPOSE: The purpose of this study was to validate the results of an 11-gene expression profiling (GEP) assay which aims to improve the precision of individual prognosis beyond conventional American Joint Committee on Cancer staging for patients with cutaneous melanoma. METHODS: The reverse transcriptase polymerase chain reaction test of 11 prospectively selected genes was performed on 291 formalin-fixed, paraffin-embedded primary tumours of patients with stage I-III cutaneous melanoma. The expression levels of eight prognostic and three reference genes were used in a predefined algorithm to calculate a numerical score (-0.84 to 3.53) and then assign each patient to a preselected risk group (low versus high score) for melanoma-specific survival (MSS). RESULTS: One hundred twenty-seven patients were allocated to the low-score group, with a corresponding five-year disease-free survival (DFS) and MSS of 95% and 99%, respectively. 164 patients were allocated to the high-score group, with a corresponding five-year DFS and MSS of 78% and 88%. Continuous regression analysis demonstrated decreasing MSS probabilities with increasing scores. In a multivariate cox regression, only the 11-GEP, tumour thickness and age were statistically associated with MSS (p = 0.0068, 0.002 and 0.0159). CONCLUSIONS: The 11-GEP has been validated as an independent predictor of outcome for melanoma patients. More specifically, using an 11-GEP score cut-off of ≤0, the assay can identify patient cohorts with 10-year survival probabilities well above 90%. This information may be used in the decision-making for a potential adjuvant therapy.

Photodynamic therapy with a 5-ALA patch does not increase the risk of conversion of actinic keratoses into squamous cell carcinoma: Results of a multicentre non-interventional study.

BACKGROUND: It is important to collect data about the risk of transformation of an actinic keratosis (AK) lesion into squamous cell carcinoma (SCC) after a single photodynamic therapy (PDT) with 5-ALA patch for a longer follow-up period under daily routine. QUESTIONS ADDRESSED: The purpose of this non-interventional study (NIS) was to collect data on the frequency of occurrence of SCCs in the treated area during an interval of 2 years after a single 5-ALA patch-PDT. EXPERIMENTAL DESIGN: This prospective observational case-only study included patients with mild AK lesions on the head and face treated with 5-ALA patch-PDT according to the Summary of Product Characteristics (SPC). RESULTS: In 370 patients, the risk of transformation of their treated AK lesion into SCC was 0.073% with its exact 95% confidence interval using the Poisson distribution of [0.009%, 0.262%]. The rate of complete clinical clearance on lesion basis after 3 months was 84.3%. CONCLUSION: The efficacy and the safety results show no observation of an increased risk for conversion of an AK into a SCC 2 years after a single 5-ALA patch-PDT. Additionally, the high clinical complete remission rate under routine conditions is comparable to the rates observed in the approval trials.

A review of BF-200 ALA for the photodynamic treatment of mild-to-moderate actinic keratosis.

BF-200 ALA is a combination of a nanoscale-lipid vesicle formulation and the prodrug 5-aminolevulinic acid (5-ALA). The nanoemulsion stabilizes the prodrug and enhances its penetration through the stratum corneum. It has shown excellent therapeutic results in both lesion and field-directed photodynamic therapy of actinic keratosis (AK). AK is an early form of epidermal neoplasia and a precursor of invasive cutaneous squamous cell carcinoma. It is characterized by the combination of visible neoplastic lesions and surrounding tissue also harboring tumorigenic UV-induced mutations: a concept called field cancerization. A selective, field-directed treatment is ideal to meet the requirements of field change. Here, we review the clinical data on BF-200 ALA for AK along with a summary of molecular mechanisms and future perspectives.

Optical coherence tomography: its role in daily dermatological practice.

Optical coherence tomography (OCT) is a non-invasive, tomographic imaging technique which generates high-resolution in-vivo images up to mid-dermal layers. Due to continuous technological improvements, OCT is moving from research projects into daily dermatological practice. It can complement other imaging methods like high-frequency ultrasound or confocal microscopy. There is a wide variety of indications for OCT. In addition to aiding in the diagnosis and clinical monitoring of inflammatory dermatoses, OCT is a very useful and feasible technique in dermato-oncology.

Electrical impedance spectroscopy as a potential adjunct diagnostic tool for cutaneous melanoma.

BACKGROUND: Previous studies have shown statistically significant differences in electrical impedance between various cutaneous lesions. Electrical impedance spectroscopy (EIS) may therefore be able to aid clinicians in differentiating between benign and malignant skin lesions. OBJECTIVES: The aim of the study was to develop a classification algorithm to distinguish between melanoma and benign lesions of the skin with a sensitivity of at least 98% and a specificity approximately 20 per cent higher than the diagnostic accuracy of dermatologists. PATIENTS/METHODS: A total of 1300 lesions were collected in a multicentre, prospective, non-randomized clinical trial from 19 centres around Europe. All lesions were excised and subsequently evaluated independently by a panel of three expert dermatopathologists. From the data two classification algorithms were developed and verified. RESULTS: For the first classification algorithm, approximately 40% of the data were used for calibration and 60% for testing. The observed sensitivity for melanoma was 98.1% (101/103), non-melanoma skin cancer 100% (25/25) and dysplastic nevus with severe atypia 84.2% (32/38). The overall observed specificity was 23.6% (66/280). For the second classification algorithm, approximately 55% of the data were used for calibration. The observed sensitivity for melanoma was 99.4% (161/162), for non-melanoma skin cancer was 98.0% (49/50) and dysplastic nevus with severe atypia was 93.8% (60/64). The overall observed specificity was 24.5% (116/474). CONCLUSION: EIS has the potential to be an adjunct diagnostic tool to help clinicians differentiate between benign and malignant (melanocytic and non-melanocytic) skin lesions. Further studies are needed to confirm the validity of the automatic assessment algorithm.

Vitamin D supply: from sun or pill? - Attitudes and recommendation on vitamin D and impact on sun protection practices among German general practitioners evaluated by the network of dermato-oncologists, Onkoderm e.V.

Recommendations concerning the intake of vitamin D and/or sunlight exposure in the handling of patients with vitamin D deficiency remain a matter of debate. The present study of the German network of dermato-oncologists (Onkoderm e.V.) refers to an inquiry conducted among general practitioners on this and related issues. Based on 448 answers provided to 10 distinct questions, the consulted physicians recommended vitamin D intake (94% replies) and/or exposure to sunlight (63% replies) in their patients with vitamin D deficiency. An average of approximately 26 min daily unprotected exposure to sunlight at midday in spring and summer was recommended. Nevertheless, 91% of the physicians considered the use of creams protecting against sunlight to be judicious. However, only 54% of physicians considered it worthwhile practice to protect oneself intensively against UV radiation. This study indicates evidence of a reduction in sun protection practices. Yet, approximately 25% of the patients were considered to present vitamin D deficiency and, hence, recommendations to prevent or correct the latter situation should not be ignored. Nevertheless, we consider that there is a need to focus messages regarding sun exposure and for continued sun protection practices. These messages should specifically focus on the vitamin D issue to ensure that the incidence of skin cancer does not increase.

Electrochemotherapy for primary skin cancer and skin metastasis related to other malignancies.

Electrochemotherapy is an effective local tumor ablation modality in the treatment of solid cancers. Its use combines the administration of nonpermeable or poorly permeable highly intrinsic cytotoxic drugs with the application of short and intense electric pulses to the tumors to facilitate the drug delivery into the cancer cells. After several preclinical and clinical studies using different and nonhomogenous protocols, the results of the multicenter European Standard Operating Procedure of Electrochemotherapy (ESOPE) project provided clinical procedures for a standardized, efficient, and safe electric pulse and drug administration protocol for the local treatment of any type of skin tumor nodules. Additional studies using the the multicenter European Standard Operating Procedure of Electrochemotherapy standard operating procedures confirmed the overall clinical results obtained. Currently, the tumors most frequently treated with ECT are melanoma and breast cancer metastasis, but also head and neck cancer, primary tumors of the skin, and Kaposi sarcoma. This review is intended as an update on the therapy and as an indication of possible future developments.

Activity of mevalonate pathway inhibitors against breast and ovarian cancers in the ATP-based tumour chemosensitivity assay.

Previous data suggest that lipophilic statins such as fluvastatin and N-bisphosphonates such as zoledronic acid, both inhibitors of the mevalonate metabolic pathway, have anti-cancer effects in vitro and in patients. We have examined the effect of fluvastatin alone and in combination with zoledronic acid in the ATP-based tumour chemosensitivity assay (ATP-TCA) for effects on breast and ovarian cancer tumour-derived cells. Both zoledronic acid and fluvastatin showed activity in the ATP-TCA against breast and ovarian cancer, though fluvastatin alone was less active, particularly against breast cancer. The combination of zoledronic acid and fluvastatin was more active than either single agent in the ATP-TCA with some synergy against breast and ovarian cancer tumour-derived cells. Sequential drug experiments showed that pre-treatment of ovarian tumour cells with fluvastatin resulted in decreased sensitivity to zoledronic acid. Addition of mevalonate pathway components with zoledronic acid with or without fluvastatin showed little effect, while mevalonate did reduced inhibition due to fluvastatin. These data suggest that the combination of zoledronic acid and fluvastatin may have activity against breast and ovarian cancer based on direct anti-cancer cell effects. A clinical trial to test this is in preparation.

Circulating 25-hydroxyvitamin D concentration in German cancer patients.

The serum 25-hydroxyvitamin D [25(OH)D] concentration was measured in 20 patients with prostatic carcinoma, compared to 75 subjects with prostatic hyperplasia, in 24 male and 17 female patients with melanoma, in 26 female patients with breast cancer, 7 patients with ovarian carcinoma and 3 patients with cervix carcinoma among subjects followed in a German polyclinical centre. In >50% of these 174 subjects, 25(OH)D concentration was < 20 microg/l. In most subject groups, a seasonal decrease of 25(OH)D concentration was observed during the winter period. An age-related decrease in such a concentration was also observed in subjects with prostatic hyperplasia examined in the late summer/early autumn period and in female cancer subjects, at the exclusion of patients with breast cancer. In the latter patients, however, a positive correlation prevailed between age and 25(OH)D concentration. Hence, it is proposed that an abnormally low serum 25(OH)D concentration represents a preferential risk factor, in middle-aged women, for breast cancer, as compared to other neoplasic manifestations in female subjects.

Evidence-based and interdisciplinary consensus-based German guidelines: systemic medical treatment of melanoma in the adjuvant and palliative setting.

Systemic medical treatment of melanoma is administered in the adjuvant and palliative setting. Adjuvant therapy may be considered in patients with primary melanoma with more than 1.5 mm tumor thickness and with regional node metastasis. Presently no indication for systemic adjuvant chemotherapy or for adjuvant therapy with nonspecific immune-stimulatory agents outside controlled studies is seen. Interferon-alpha is the first substance in the adjuvant therapy of melanoma, which has shown to present a significant advantage to the patients in some prospective randomized studies. Good arguments for using adjuvant interferon-alpha therapy in high-risk melanoma patients exist. Both high-dose and low-dose interferon-alpha show promise. The major indications for systemic chemotherapy and chemoimmunotherapy are inoperable recurrent tumors, inoperable regional metastases and distant metastases (stage IV). As treatment in such situations is primarily palliative, the effect of any regimen on the quality of life must be carefully weighed. As a first line treatment, single agent therapy is recommended, as polychemotherapy or biochemotherapy did not show significant advantages for prolongation of survival; hence they are more toxic. An urgent need for development of new treatment modalities is necessary and general principles of experimental immunotherapy are outlined.

Evidence and interdisciplinary consensus-based German guidelines: surgical treatment and radiotherapy of melanoma.

The primary treatment of a melanoma is surgical excision. An excisional biopsy is preferred, and safety margins of 1 cm for tumor thickness up to 2 mm and 2 cm for higher tumor thickness should be applied either at primary excision or in a two-step procedure. When dealing with facial, acral or anogenital melanomas, micrographic control of the surgical margins may be preferable to allow reduced safety margins and conservation of tissue. The sentinel lymph node biopsy should be performed in patients whose primary melanoma is thicker than 1.0 mm and this operation should be performed in centers where both the operative and nuclear medicine teams are experienced. In clinically identified lymph node metastases, radical lymph node dissection is considered standard therapy. If distant metastases involve just one internal organ and operative removal is feasible, then surgery should be seen as therapy of choice. Radiation therapy for the primary treatment of melanoma is indicated only in those cases in which surgery is impossible or not reasonable. In regional lymph nodes, radiation therapy is usually recommended when excision is not complete (R1 resection) or if the nodes are inoperable. In distant metastases, radiation therapy is particularly indicated in bone metastases, brain metastases and soft tissue metastases.

Evidence and interdisciplinary consense-based German guidelines: diagnosis and surveillance of melanoma.

Melanoma is a malignant tumor that arises from melanocytic cells and primarily involves the skin. The most important exogenous etiological factor is exposure to ultraviolet irradiation. Diagnosis of melanoma is based primarily on its clinical features, and the A-B-C-D rule is useful in identifying pigmented lesions, which are suspicious for melanoma (Asymmetry, Border irregular, Color inhomogeneous and Diameter more than 5 mm). Dermoscopy is very helpful in clarifying the differential diagnosis of pigmented lesions. About 90% of melanomas are diagnosed as primary tumors without any evidence for metastasis. The tumor-specific 10-year survival for all such tumors is about 75-85%. The most important prognostic factors for primary melanoma without metastases are vertical tumor thickness (Breslow depth) as measured on the histological specimen, presence of histopathologically recognized ulceration, invasion level (Clark level) and identification of micrometastases in the regional lymph nodes via sentinel lymph node biopsy. The current tumor node metastasis classification for the staging of primary melanoma is based on these factors. Melanomas can metastasize either by the lymphatic or by the hematogenous route. About two-thirds of metastases are originally confined to the drainage area of regional lymph nodes. A regional metastasis can appear as satellite metastases up to 2 cm from the primary tumor, as intransit metastases in the skin between the site of the primary tumor and the first lymph node and as regional lymph node metastases. In the stage of regional metastasis, the differentiation between micrometastasis and macrometastasis and the number of lymph nodes involved are crucial. As soon as distant metastasis develops, prognosis depends on the site of the metastasis and on the lactate dehydrogenase levels in the blood. The frequency and extent of follow-up examinations is based on the initial tumor parameters. In thin primary melanomas up to 1-mm tumor thickness, clinical examinations at 6-month intervals are sufficient and in thicker primary melanomas, at 3-month intervals. Lymph node sonography as well as determination of the tumor marker protein S100beta are recommended. Additionally, in the stage of regional metastasis, whole body imaging should be performed every 6 months; in the stage of distant metastasis, surveillance has to be scheduled individually.

[Efalizumab--therapy of moderately severe to severe plaque-psoriasis in the dermatologist's practice]. / Efalizumab-Therapie der mittelschweren bis schweren Plaque-Psoriasis in der Hautarztpraxis.

Psoriasis is a chronic immune-mediated skin disease with highly variable patterns of presentation, both between patients and in individuals over time. Its course can be influenced by various triggers. Since there is no cure for psoriasis, patients with moderate-to-severe plaque-type psoriasis often require lifelong therapy to control their disease. Traditional approaches such as cyclosporine or methotrexate are problematic for long-term use because of organ toxicity, other side effects, drug interactions and a loss of efficacy over time. Efalizumab is a recombinant monoclonal IgG1-antibody, approved in Germany for the management of moderate-to-severe plaque-type psoriasis. Its efficacy and safety have been demonstrated in clinical trials with thousands of patients,especially with regard to long-term therapy. Therefore, a change of paradigm from the traditional therapy of inflammatory episodes to continuous control of psoriasis seems possible. This supplement deals with practical aspects of using efalizumab in the outpatient setting.

In vitro drug sensitivity predicts response and survival after individualized sensitivity-directed chemotherapy in metastatic melanoma: a multicenter phase II trial of the Dermatologic Cooperative Oncology Group.

PURPOSE: In vitro sensitivity assays are promising tools to predict the individual outcome of different chemotherapy regimens. However, a direct association between in vitro and in vivo chemosensitivity has to be shown by clinical studies. This multicenter phase II trial was aimed to investigate the efficacy of a sensitivity-directed, first-line chemotherapy in metastasized melanoma patients, and to prove an association between in vitro sensitivity and therapy outcome. PATIENTS AND METHODS: The primary study end point was objective response; secondary end points were safety, overall survival, and progression-free survival. Viable tumor cells obtained from metastatic lesions were tested for chemosensitivity to seven single drugs and five drug combinations using an ATP-based luminescence viability assay. RESULTS: Out of 82 recruited patients (intention-to-treat), 57 received assay-directed chemotherapy and 53 were evaluable for all study end points (per protocol). The drug combinations used were gemcitabine+treosulfan, paclitaxel+cisplatin, paclitaxel+doxorubicin, and gemcitabine+cisplatin. The per protocol population could be divided into 22 (42%) chemosensitive and 31 (58%) chemoresistant patients by an arbitrary chemosensitivity index. Objective response was 36.4% in chemosensitive patients compared with 16.1% in chemoresistant patients (P=0.114); progression arrest (complete response+partial response+stable disease) was 59.1% versus 22.6% (P=0.01). Chemosensitive patients showed an increased overall survival of 14.6 months compared with 7.4 months in chemoresistant patients (P=0.041). CONCLUSION: In vitro chemosensitivity testing may be worthy of further exploration to see if it could be a useful tool to predict the outcome of melanoma patients treated with a sensitivity-directed chemotherapy. Therefore, these preliminary results will be evaluated by a planned phase III trial using a randomized, standard-regimen controlled setting.