Summary
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.
What's already known about this topic?
Photodynamic therapy (PDT) using BF‐200 aminolaevulinic acid (ALA) gel is registered and highly effective in the treatment of mild‐to‐moderate actinic keratosis and field cancerization.
BF‐200 ALA gel was recently approved for the treatment of superficial and/or nodular basal cell carcinoma (BCC) unsuitable for surgical treatment.
PDT using methyl aminolaevulinate (MAL) cream is approved for the treatment of thin or nonhyperkeratotic and nonpigmented actinic keratoses, Bowen disease, and superficial and nodular BCCs when other therapies are considered less appropriate.
What does this study add?
BF‐200 ALA‐PDT is confirmed to be significantly noninferior to MAL‐PDT for the treatment of nonaggressive BCC.
Treatment‐emergent adverse events were comparable between the two patient groups, with similar or slightly lower recurrence rates for BF‐200 ALA gel compared with MAL cream after 12 months.
Plain language summary available online
Respond to this article
Summary
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 3 months 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 3 months 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.
See also the Commentary by Hauschild
Summary 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.
What’s already known about this topic?
•
BF‐200 ALA is a stable nanoemulsion‐based gel formulation of 5‐aminolaevulinic acid (ALA) for photodynamic therapy (PDT) of actinic keratosis (AK), which demonstrated significantly higher efficacy compared with a registered methyl aminolaevulinate (MAL) cream.
What does this study add?
•
This study gives 6‐ and 12‐month follow‐up results of two pivotal phase III studies with BF‐200 ALA for PDT of AK in comparison to placebo and a registered MAL cream.
•
It provides a comparison of recurrence rates after use of different light sources for PDT of AK.
See also the Commentary by Babilas
BF‐200 ALA gel vs. MAL cream for BCC Morton, C.A.; Dominicus, R.; Radny, P. ...
British journal of dermatology (1951),
August 2018, 20180801, Letnik:
179, Številka:
2
Journal Article
Recenzirano
Summary
Basal cell carcinoma (BCC), also known as rodent ulcer, is the most common type of non‐melanoma skin cancer worldwide. It affects about 3–10% of people. This study from the U.K. and Germany ...aimed to find out if BF‐200 ALA gel would work as well as (is non‐inferior to) the already authorised MAL cream in the treatment of non‐aggressive BCC lesions. Both medications are applied topically (on the skin) to the tumour, which is then illuminated with a certified lamp. The illumination causes a chemical reaction that affects the cancer cells so that they eventually die. This kind of procedure is called photodynamic therapy (PDT). Patients in the study were put into the two groups by chance (randomized): 138 in the BF‐200 ALA group and 143 in the MAL group. The treatment scheme for both drugs was the same. Initially, patients had two PDTs one week apart. Four and 12 weeks after the second PDT, patients visited the doctor again, who assessed the treated lesions and patient's health. If all lesions were gone by week 12, the patient entered the 5‐year follow‐up study. In case of remaining lesions, patients received two more PDTs before entering the follow‐up. During the follow‐up, doctors monitor the health of the patients and assess if any of the treated lesions come back. The study found that there was no difference between the two groups, which means that BF‐200 ALA gel worked as well as the already approved MAL cream. In 113 of 121 patients (93.4%) treated with BF‐200 ALA and 101 of 110 patients (91.8%) treated with MAL, lesions disappeared completely. 87% of the BF‐200 ALA‐treated patients rated their satisfaction with the PDT as “very good or good”; 86% of the MAL‐treated patients said the same. Almost all patients experienced mild to moderate local side effects related to the study medications. Common side effects at the application site, which affected more than 1 of 10 patients, were pain, skin reddening (erythema), itching (pruritus), and tissue swelling (oedema). Side effects were similar for both medications. At 12‐month follow‐up, lesions reappeared in 8.4% of the BF‐200 ALA‐treated patients and in 8.5% of the MAL‐treated patients. The follow‐up is still ongoing; further results will be reported after the end of the study. This study showed that BF‐200 ALA gel is as effective and well‐tolerated as MAL cream in the treatment of non‐aggressive BCC. Based on these findings, the European Medicine Agency (EMA) granted approval for BF‐200 ALA for the treatment of non‐aggressive BCC.
Linked Article: Morton et al. Br J Dermatol 2018; 179:309–319
Cidofovir is an acyclic nucleoside phosphonate with broad‐spectrum activity against DNA viruses, including human papilloma virus (HPV). However, data on the efficacy of cidofovir in an ...immunosuppressive setting remain contradictory. We report for the first time on the promotion of the healing of recalcitrant warts in a patient with myelodysplastic syndrome with intravenous cidofovir treatment.
One-dimensional, second-order finite-difference approximations of the derivative are constructed which satisfy a global conservation law. Creating a second-order approximation away from the boundary ...is simple, but obtaining appropriate behavior near the boundary is difficult, even in one dimension on a uniform grid. In this article we exhibit techniques that allow the construction of discrete versions of the divergence and gradient operator that have high-order approximations at the boundary. We construct such discretizations in the one-dimensional situation which have fourth-order approximation both on the boundary and in the interior. The precision of the high-order mimetic schemes in this article is as high as possible at the boundary points (with respect to the bandwidth parameter). This guarantees an overall high order of accuracy. Furthermore, the method described for the calculation of the approximations uses matrix analysis to streamline the various mimetic conditions. This contributes to a marked clarity with respect to earlier approaches. This is a crucial preliminary step in creating higher-order approximations of the divergence and gradient for nonuniform grids in higher dimensions.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
This paper describes how discrete versions of the derivative on the real line induce discrete version of the gradient and divergence in higher dimensions. This is geometrically motivated by results ...in algebraic graph theory since the grid in n dimensions is the graph Kronecker product of the path on n vertices. The resulting technique relies heavily on the matrix Kronecker product, and is an analogue of a derivation in multilinear algebra.
Zusammenfassung
Die Rosazea ist eine häufige chronisch-entzündliche Erkrankung der Gesichtshaut überwiegend bei erwachsenen Frauen. Nicht alle klinischen Erscheinungsformen der Erkrankung lassen sich ...mit den bisher verfügbaren Therapieoptionen ausreichend kontrollieren. In einer prospektiven, nicht-verblindeten, nicht-kontrollierten, multizentrischen Beobachtungsstudie mit 209 Patienten (davon 74,2 % Frauen) im Alter von 19 – 82 (Median 49) Jahren mit Rosazea im Stadium I – III wurde die Wirksamkeit und Verträglichkeit einer Testformulierung mit Ambophénol
®
, Neurosensine
®
und La Roche-Posay-Thermalwasser als adjuvante Therapie bei zweimal täglicher Anwendung über 8 Wochen evaluiert. Im Verlauf der Therapie nahm der Schweregrad der persistierenden Erytheme, anfallsweisen Rötungen, Flush-Reaktionen sowie subjektiven Beschwerden (Spannungsgefühl, Brennen, Juckreiz) signifikant ab (p < 0,0001). Die Verträglichkeit der Testformulierung wurde insgesamt als gut eingestuft, wobei 8,1 % der Patienten meist geringfügige Hautirritationen entwickelten und 3,8 % der Patienten die adjuvante Therapie aufgrund von Nebenwirkungen vorzeitig abbrachen. Die Studie lässt erkennen, dass die Testformulierung eine wirksame und gut verträgliche adjuvante Therapieoption für die Rosazea unabhängig von ihrem Krankheitsstadium und ihrer gegenwärtigen Therapie darstellt.