Non-melanoma skin cancer Madan, Vishal, MRCP; Lear, John T, Dr; Szeimies, Rolf-Markus, MD
The Lancet (British edition),
02/2010, Letnik:
375, Številka:
9715
Journal Article
Recenzirano
Summary The rising incidence and morbidity of non-melanoma skin cancers has generated great interest in unravelling of their pathogenesis and in the search for new non-invasive treatments. Whereas ...the role of cumulative sun exposure in pathogenesis of squamous-cell carcinoma seems clear, the relation between sun-exposure patterns and subtypes of basal-cell carcinoma remains undetermined. Several complex genotypic, phenotypic, and environmental factors contribute to pathogenesis of non-melanoma skin cancers. Unlike basal-cell carcinoma, squamous-cell carcinomas can arise from precursor lesions. Diagnosis of non-melanoma skin cancer is made clinically and confirmed by histological testing. Prognosis depends on lesion and host characteristics, which also dictate choice of treatment. Prevention strategies aim at reduction of sun exposure, but are of unproven benefit, especially for basal-cell carcinoma. Surgical excision with predetermined margins is the mainstay of treatment for squamous-cell carcinoma and for most basal-cell carcinomas. Of the new non-invasive treatments, only photodynamic therapy and topical imiquimod have become established treatments for specific subtypes of basal-cell carcinoma, and the search for more effective and tissue-salvaging therapies continues.
Summary Background Patients with advanced basal cell carcinoma have limited treatment options. Hedgehog pathway signalling is aberrantly activated in around 95% of tumours. We assessed the antitumour ...activity of sonidegib, a Hedgehog signalling inhibitor, in patients with advanced basal cell carcinoma. Methods BOLT is an ongoing multicentre, randomised, double-blind, phase 2 trial. Eligible patients had locally advanced basal cell carcinoma not amenable to curative surgery or radiation or metastatic basal cell carcinoma. Patients were randomised via an automated system in a 1:2 ratio to receive 200 mg or 800 mg oral sonidegib daily, stratified by disease, histological subtype, and geographical region. The primary endpoint was the proportion of patients who achieved an objective response, assessed in the primary efficacy analysis population (patients with fully assessable locally advanced disease and all those with metastatic disease) with data collected up to 6 months after randomisation of the last patient. This trial is registered with ClinicalTrials.gov , number NCT01327053. Findings Between July 20, 2011, and Jan 10, 2013, we enrolled 230 patients, 79 in the 200 mg sonidegib group, and 151 in the 800 mg sonidegib group. Median follow-up was 13·9 months (IQR 10·1–17·3). In the primary efficacy analysis population, 20 (36%, 95% CI 24–50) of 55 patients receiving 200 mg sonidegib and 39 (34%, 25–43) of 116 receiving 800 mg sonidegib achieved an objective response. In the 200 mg sonidegib group, 18 (43%, 95% CI 28–59) patients who achieved an objective response, as assessed by central review, were noted among the 42 with locally advanced basal cell carcinoma and two (15%, 2–45) among the 13 with metastatic disease. In the 800 mg group, 35 (38%, 95% CI 28–48) of 93 patients with locally advanced disease had an objective response, as assessed by central review, as did four (17%, 5–39) of 23 with metastatic disease. Fewer adverse events leading to dose interruptions or reductions (25 32% of 79 patients vs 90 60% of 150) or treatment discontinuation (17 22% vs 54 36%) occurred in patients in the 200 mg group than in the 800 mg group. The most common grade 3–4 adverse events were raised creatine kinase (five 6% in the 200 mg group vs 19 13% in the 800 mg group) and lipase concentration (four 5% vs eight 5%). Serious adverse events occurred in 11 (14%) of 79 patients in the 200 mg group and 45 (30%) of 150 patients in the 800 mg group. Interpretation The benefit-to-risk profile of 200 mg sonidegib might offer a new treatment option for patients with advanced basal cell carcinoma, a population that is difficult to treat. Funding Novartis Pharmaceuticals Corporation.
Basal cell carcinoma (BCC) is the most common malignancy and form of skin cancer worldwide; advanced BCC, either as locally advanced BCC (laBCC) or metastatic BCC (mBCC), can cause substantial tissue ...invasion and morbidity. Until the recent availability of the hedgehog pathway inhibitors (HHIs) sonidegib and vismodegib, treatment options for advanced BCC were limited. These agents demonstrate efficacy in patients with laBCC and mBCC; however, the adverse events (AEs) associated with these agents can lead to treatment interruption or discontinuation and reduced quality of life, all of which significantly impact long-term adherence to therapy, which might affect clinical outcome. Given that most AEs are class-related effects, switching HHIs does not appear to lead to a significantly different AE profile, underscoring the importance of maintaining patients on their first HHI. Interrupting treatment of sonidegib and vismodegib does not appear to undermine the efficacy of these agents and is therefore a practical option to manage AEs in order to maintain continued treatment and disease control.
Non-melanoma skin cancer (NMSC) is the most common malignancy among the Caucasian population. Photodynamic therapy (PDT) is gaining popularity for the treatment of basal cell carcinoma (BCC), Bowen's ...disease (BD) and actinic keratosis (AK). A topical or systemic exogenous photosensitiser, results in selective uptake by malignant cells. Protoporphyrin IX (PpIX) is produced then activated by the introduction of a light source. Daylight-mediated MAL (methyl aminolaevulinate) PDT for AKs has the advantage of decreased pain and better patient tolerance. PDT is an effective treatment for superficial BCC, BD and both individual and field treatment of AKs. Excellent cosmesis can be achieved with high patient satisfaction. Variable results have been reported for nodular BCC, with improved outcomes following pretreatment and repeated PDT cycles. The more aggressive basisquamous, morphoeic infiltrating subtypes of BCC and invasive squamous cell carcinoma (SCC) are not suitable for PDT. Prevention of "field cancerization" in organ transplant recipients on long-term immunosuppression and patients with Gorlin syndrome (naevoid basal cell carcinoma syndrome) is a promising development. The optimisation of PDT techniques with improved photosensitiser delivery to target tissues, new generation photosensitisers and novel light sources may expand the future role of PDT in NMSC management.
•Outcomes for patients with advanced basal cell carcinoma (BCC) are relatively poor.•Hedgehog pathway inhibitors are a promising treatment option for advanced BCC.•Emerging data may help physicians ...to better define and treat advanced BCC.
Basal cell carcinoma (BCC) is the most commonly diagnosed skin cancer worldwide. In most patients, BCC can be effectively treated with standard surgical excision, Mohs micrographic surgery, curettage and electrodessication, radiotherapy, and/or superficial field therapies (including 5-fluorouracil, imiquimod, and photodynamic therapy); however, a minority of patients develop advanced BCC, for which treatment can be challenging and outcomes are poorer. Advanced BCC encompasses a heterogeneous assortment of cases, including metastatic BCC as well as locally advanced BCC (for which no formal definition exists but which generally includes large, deep, aggressive, or recurrent tumors). Locally advanced BCC may be broadly categorized as cases for which (further) surgery is considered inappropriate or would be substantially disfiguring and radiation is considered inappropriate as a single modality or second-line treatment. Several therapies are being investigated for the treatment of advanced BCC. In particular, hedgehog pathway inhibitors have emerged as an important treatment option for this population. Two hedgehog pathway inhibitors—vismodegib and sonidegib—have received regulatory approval for the treatment of certain subsets of patients with advanced BCC after demonstrating clinical efficacy and safety in large, international phase 2 clinical trials. Here we review the available treatment options for BCC, focusing on the treatment of advanced BCC. Clinical data from studies evaluating vismodegib and sonidegib in patients with advanced BCC are also discussed. As more clinical trial and real-world data on the use of hedgehog pathway inhibitors become available, better-informed decisions can be made for the treatment of patients with advanced BCC.
Background The hedgehog pathway inhibitor sonidegib demonstrated meaningful tumor shrinkage in more than 90% of patients with locally advanced basal cell carcinoma (BCC) or metastatic BCC in the BCC ...Outcomes with LDE225 Treatment study. Objective This report provides long-term follow-up data collected up to 12 months after the last patient was randomized. Methods In this multicenter, randomized, double-blind phase II study, patients were randomized 1:2 to sonidegib 200 or 800 mg. The primary end point was objective response rate assessed by central review. Results Objective response rates in the 200- and 800-mg arms were 57.6% and 43.8% in locally advanced BCC and 7.7% and 17.4% in metastatic BCC, respectively. Among the 94 patients with locally advanced BCC who responded, only 18 progressed or died and more than 50% had responses lasting longer than 6 months. In addition, 4 of 5 responders with metastatic BCC maintained an objective response. Grade 3/4 adverse events and those leading to discontinuation were less frequent with sonidegib 200 versus 800 mg (38.0% vs 59.3%; 27.8% vs 37.3%, respectively). Limitations No placebo or comparator arms were used because sonidegib demonstrated efficacy in advanced BCC in a phase I study, and the hedgehog pathway inhibitor vismodegib was not yet approved. Conclusion With longer follow-up, sonidegib demonstrated sustained tumor responses in patients with advanced BCC.
Non-melanoma skin cancer Griffin, Liezel L; Ali, Faisal Rehman; Lear, John T
Clinical medicine (London, England),
February 2016, 2016-Feb, 2016-02-00, 20160201, Letnik:
16, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Non-melanoma skin cancer (NMSC) comprises basal cell carcinoma (BCC) and squamous cell carcinoma, together with a host of rare tumours. NMSC is the commonest malignancy among Caucasians and its ...incidence continues to rise annually. Exposure to UV radiation initiates approximately 90% of NMSC, causing malignant transformation of keratinocytes and suppression of the inflammatory response. Risk factors include sun exposure and immunosuppression. There are several subtypes of BCC, although histological overlap is common. Surgery has traditionally been regarded as the ‘gold-standard’ treatment, offering excellent cure rates and cosmetic results. Other treatment modalities include physical destruction (radiotherapy, curettage and cautery, and cryotherapy), chemical destruction (photodynamic therapy and topical 5-flurouracil) and immunomodulatory therapy (topical imiquimod). The recent development of novel hedgehog pathway inhibitors for high-risk BCC (including oral vismodegib and sonidegib) may represent a paradigm shift towards medical management of NMSC.
Actinic keratosis (AK) lesions are surrounded by field cancerization (areas of subclinical, non-visible sun damage). Existing AK grading tools rely on AK counts, which are not reproducible. An ...Actinic Keratosis Field Assessment Scale (AK-FAS) for grading the severity of AK/field was developed. Standardized photographs of patients representing the full range of AK severity were collected. Six investigators independently rated each photograph according to 3 criteria: AK area (total skin area affected by AK lesions), hyperkeratosis and sun damage. Inter-rater reproducibility was good for all 3 criteria. Validation of the AK-FAS showed good reproducibility for AK area and hyperkeratosis, even for dermatologists untrained on use of the scale. In conclusion, the AK-FAS is objective, easy to use and implement, and reproducible. It incorporates assessment of the entire field affected by AK instead of relying on lesion counts. Use of the AK-FAS may standardize AK diagnosis, making it relevant to routine clinical practice.
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