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.
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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
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) α2a with or without dacarbazine (DTIC) compared with observation alone.
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 IFNα2a three times a week for 2 years (Arm A) or combined treatment with same doses of IFNα2a plus DTIC 850 mg/m2 every 4–8 weeks for 2 years (Arm B) or to observation alone (Arm C). Treatment was discontinued at first sign of relapse.
A total of 441 patients were eligible for intention-to-treat analysis. Kaplan–Meier 4-year OS rate of those who had received IFNα2a 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).
3 MU interferon α2a 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 α2a therapy.
Summary
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.
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) alpha 2a 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 IFN alpha 2a three times a week for 2 years (Arm A) or combined treatment with same doses of IFN alpha 2a plus DTIC 850 mg/m super(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 IFN alpha 2a 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 alpha 2a 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 alpha 2a therapy.
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
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.
We undertook a systematic review of 41 randomised studies in disseminated melanoma, identified by a comprehensive search. We aimed to investigate rates of response to various treatment modalities and ...the outcome for the patients. We analysed seven studies that compared polychemotherapy with single-agent dacarbazine, six that compared different chemotherapeutic schedules with each other, five on the addition of tamoxifen to a reference therapy, and six that included non-specific immunostimulators. In 17 studies, the addition of interferon alfa, interleukin 2, or both, to a reference therapy was investigated, including trials with biochemotherapy. Many trials had small sample sizes and did not report a power analysis; not all were analysed by intention to treat. Although some treatment regimens, especially polychemotherapeutic schedules, seem to increase response rates, none of the treatment schedules was proven to prolong overall survival. Patients with disseminated melanoma should be treated with well-tolerated drug regimens, such as single-agent treatments or in combination with interferon alfa. Systemic treatments should preferably be investigated in randomised trials so that the potential benefits of new treatment concepts can be thoroughly examined.
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