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Basal cell carcinoma (BCC), the most common type of skin cancer, is characterized by aberrant activation of the hedgehog molecular pathway. Systemic therapy is indicated when local approaches, such as surgery and radiation, are inappropriate. In this article, a group of clinical experts recommends the long-term management strategy for advanced BCC patients treated with systemic therapy. The hedgehog inhibitors sonidegib and vismodegib are first-line treatments for advanced BCC with a long-lasting response, but long-term treatment with hedgehog inhibitors is often challenged by tolerability issues. However, several strategies for adverse effect management are available, such as dose interruptions, on-label alternate-day dosing and supportive medications. In conclusion, although BCC shows a high tumor mutational burden that favors a response to immunotherapy, experts recommend keeping patients on hedgehog inhibitors limiting immunotherapy to those who developed resistance during hedgehog inhibitor therapy or in case of persisting toxicity despite long-term management of adverse events.

Cutaneous melanoma (CM) is potentially the most dangerous form of skin tumor and causes 90% of skin cancer mortality. A unique collaboration of multi-disciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization for Research and Treatment of Cancer (EORTC) was formed to make recommendations on CM diagnosis and treatment, based on systematic literature reviews and the experts' experience. The diagnosis of melanoma can be made clinically and shall always be confirmed with dermatoscopy. If a melanoma is suspected, a histopathological examination is always required. Sequential digital dermatoscopy and full body photography can be used in high-risk patients to improve the detection of early melanoma. Where available, confocal reflectance microscopy can also improve clinical diagnosis in special cases. Melanoma shall be classified according to the 8th version of the American Joint Committee on Cancer classification. Thin melanomas up to 0.8 mm tumor thickness do not require further imaging diagnostics. From stage IB onwards, examinations with lymph node sonography are recommended, but no further imaging examinations. From stage IIC onwards whole-body examinations with computed tomography (CT) or positron emission tomography CT (PET-CT) in combination with brain magnetic resonance imaging are recommended. From stage III and higher, mutation testing is recommended, particularly for BRAF V600 mutation. It is important to provide a structured follow-up to detect relapses and secondary primary melanomas as early as possible. There is no evidence to define the frequency and extent of examinations. A stage-based follow-up scheme is proposed which, according to the experience of the guideline group, covers the optimal requirements, but further studies may be considered. This guideline is valid until the end of 2024.

Background: No simple staging system has emerged for basal cell carcinomas (BCCs), since they do not follow the TNM process, and practitioners failed to agree on simple clinical or pathological criteria as a basis for a classification. Operational classification of BCCs is required for decision-making, trials and guidelines. Unsupervised clustering of real cases of difficult-to-treat BCCs (DTT-BCCs; part 1) has demonstrated that experts could blindly agree on a five groups classification of DTT-BCCs based on five patterns of clinical situations. Objective: Using this five patterns to generate an operational and comprehensive classification of BCCs. Method: Testing practitioner's agreement, when using the five patterns classification to ensure that it is robust enough to be used in the practice. Generating the first version of a staging system of BCCs based on pattern recognition. Results: Sixty-two physicians, including 48 practitioners and the 14 experts who participated in the generation of the five different patterns of DTT-BCCs, agreed on 90% of cases when classifying 199 DTT-BCCs cases using the five patterns classification (part 1) attesting that this classification is understandable and usable in practice. In order to cover the whole field of BCCs, these five groups of DTT-BCCs were added a group representing the huge number of easy-to-treat BCCs, for which sub-classification has little interest, and a group of very rare metastatic cases, resulting in a four-stage and seven-substage staging system of BCCs. Conclusion: A practical classification adapted to the specificities of BCCs is proposed. It is the first tumour classification based on pattern recognition of clinical situations, which proves to be consistent and usable. This EADO staging system version 1 will be improved step by step and tested as a decision tool and a prognostic instrument.

Background: Before February, 2021, there was no standard treatment regimen for locally advanced basal cell carcinoma after first-line hedgehog inhibitor (HHI) therapy. Cemiplimab, a PD-1 antibody, is approved for treatment of advanced cutaneous squamous cell carcinoma and has shown clinical activity as monotherapy in first-line non-small-cell lung cancer. Here, we present the primary analysis data of cemiplimab in patients with locally advanced basal cell carcinoma after HHI therapy. Methods: We did an open-label, multicentre, single-arm, phase 2 trial across 38 outpatient clinics, primarily at academic medical centres, in Canada, Europe, and the USA. Eligible patients (aged ≥18 years and with an Eastern Cooperative Oncology Group performance status of 0 or 1) with a histologically confirmed diagnosis of metastatic basal cell carcinoma (group 1) or locally advanced basal cell carcinoma (group 2) who had progressed on or were intolerant to previous HHI therapy were enrolled. Patients were not candidates for further HHI therapy due to progression of disease on or intolerance to previous HHI therapy or having no better than stable disease after 9 months on HHI therapy. Patients received cemiplimab 350 mg intravenously every 3 weeks for up to 93 weeks or until progression or unacceptable toxicity. The primary endpoint was objective response by independent central review. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. The primary analysis is reported only for group 2; group 1 data have not reached maturity and will be reported when the timepoint, according to the statistical analysis plan, has been reached. This study is registered with ClinicalTrials.gov, NCT03132636, and is no longer recruiting new participants. Findings: Between Nov 16, 2017, and Jan 7, 2019, 84 patients were enrolled and treated with cemiplimab. At data cutoff on Feb 17, 2020, median duration of foll

Background: No simple classification system has emerged for ‘advanced basal cell carcinomas’, and more generally for all difficult-to-treat BCCs (DTT-BCCs), due to the heterogeneity of situations, TNM inappropriateness to BCCs, and different approaches of different specialists. Objective: To generate an operational classification, using the unconscious ability of experts to simplify the great heterogeneity of the clinical situations into a few relevant groups, which drive their treatment decisions. Method: Non-supervised independent and blinded clustering of real clinical cases of DTT-BCCs was used. Fourteen international experts from different specialties independently partitioned 199 patient cases considered ‘difficult to treat’ into as many clusters they want (≤10), choosing their own criteria for partitioning. Convergences and divergences between the individual partitions were analyzed using the similarity matrix, K-mean approach, and average silhouette method. Results: There was a rather consensual clustering of cases, regardless of the specialty and nationality of the experts. Mathematical analysis showed that consensus between experts was best represented by a partition of DTT-BCCs into five clusters, easily recognized a posteriori as five clear-cut patterns of clinical situations. The concept of ‘locally advanced’ did not appear consistent between experts. Conclusion: Although convergence between experts was not granted, this experiment shows that clinicians dealing with BCCs all tend to work by a similar pattern recognition based on the overall analysis of the situation. This study thus provides the first consensual classification of DTT-BCCs. This experimental approach using mathematical analysis of independent and blinded clustering of cases by experts can probably be applied to many other situations in dermatology and oncology.

Sonidegib and vismodegib are hedgehog pathway inhibitors (HhIs) approved for the treatment of advanced basal cell carcinoma (BCC). Until recently, vismodegib was the only targeted treatment available for patients with locally advanced BCC (laBCC) in cases where surgery and radiotherapy are inappropriate. Sonidegib has recently been approved and now presents an alternative treatment option. The clinical differences between the two HhIs in patients with laBCC are unclear, as no head-to-head randomized controlled trials are or will be initiated. Moreover, there were important differences in the designs of their pivotal studies, BOLT (sonidegib) and ERIVANCE (vismodegib), and these differences complicate evidence-based analysis of their relative efficacy and safety profiles. In this paper, a group of clinical experts in the management of laBCC summarizes the clinical and pharmacological profiles of sonidegib and vismodegib based on published data and their own clinical experience. One key difference between the two pivotal studies was the criteria used to assess BCC severity. ERIVANCE (a single-arm phase II trial) used the conventional Response Evaluation Criteria in Solid Tumors (RECIST), while the more recent double-blind randomized BOLT trial used the stringent modified RECIST (mRECIST). A pre-planned analysis adjusted the outcomes from BOLT with RECIST-like criteria and this enabled the experts to discuss relative efficacy outcomes for the two treatments. Centrally reviewed objective response rate (ORR) for vismodegib was 47.6% (95% CI 35.5-60.6) at 21-month follow-up using RECIST. After adjusting with RECIST-like criteria, the ORR for sonidegib according to central review at 18-month follow-up was 60.6% (95% CI 47.8-72.4). Both treatments were associated with similar patterns of adverse events. Sonidegib and vismodegib share the same efficacy and tolerability profiles, but their pharmacokinetic profiles show several differences, such as volume of distribution and h

Topical photodynamic therapy (PDT) is a widely approved therapy for actinic keratoses, Bowen's disease (squamous cell carcinoma in situ), superficial and certain thin basal cell carcinomas. Recurrence rates when standard treatment protocols are used are typically equivalent to existing therapies, although inferior to surgery for nodular basal cell carcinoma. PDT can be used both as lesional and field therapies and has the potential to delay/reduce the development of new lesions. A protocol using daylight to treat actinic keratoses is widely practised, with conventional PDT using a red light after typically a 3-h period of occlusion employed for other superficial skin cancer indications as well as for actinic keratoses when daylight therapy is not feasible. PDT is a well-tolerated therapy although discomfort associated with conventional protocol may require pain-reduction measures. PDT using daylight is associated with no or minimal pain and preferred by patient. There is an emerging literature on enhancing conventional PDT protocols or combined PDT with another treatment to increase response rates. This guideline, published over two parts, considers all current approved and emerging indications for the use of topical PDT in dermatology, prepared by the PDT subgroup of the European Dermatology Forum guidelines committee. It presents consensual expert recommendations reflecting current published evidence.

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© 2017 The Author(s). Background: In the primary analysis of the ERIVANCE BCC trial, vismodegib, the first US Food and Drug Administration-approved Hedgehog pathway inhibitor, showed objective response rates (ORRs) by independent review facility (IRF) of 30% and 43% in metastatic basal cell carcinoma (mBCC) and locally advanced BCC (laBCC), respectively. ORRs by investigator review were 45% (mBCC) and 60% (laBCC). Herein, we present long-term safety and final investigator-assessed efficacy results in patients with mBCC or laBCC. Methods: One hundred four patients with measurable advanced BCC received oral vismodegib 150 mg once daily until disease progression or intolerable toxicity. The primary end point was IRF-assessed ORR. Secondary end points included ORR, duration of response (DOR), progression-free survival, overall survival (OS), and safety. Results: At data cutoff (39 months after completion of accrual), 8 patients were receiving the study drug (69 patients in survival follow-up). Investigator-assessed ORR was 48.5% in the mBCC group (all partial responses) and 60.3% in the laBCC group (20 patients had complete response and 18 patients had partial response). ORRs were comparable across patient subgroups, including aggressive histologic subtypes (eg, infiltrative BCC). Median DOR was 14.8 months (mBCC) and 26.2 months (laBCC). Median OS was 33.4 months in the mBCC cohort and not estimable in the laBCC cohort. Adverse events remained consistent with clinical experience. Thirty-three deaths (31.7%) were reported; none were related to vismodegib. Conclusions: This long-term update of the ERIVANCE BCC trial demonstrated durability of response, efficacy across patient subgroups, and manageable long-term safety of vismodegib in patients with advanced BCC. Trial registration: This study was registered prospectively with Clinicaltrials.gov , number NCT00833417on January 30, 2009.

BACKGROUND: Topical therapy is important in the treatment of actinic keratosis, but guidance for improving adherence/persistence during topical therapy is still lacking. OBJECTIVES: To utilize expert consensus to generate a list of recommendations to improve real-world efficacy when prescribing topical therapy for actinic keratosis. METHODS: An expert panel of eight dermatologists was convened to generate recommendations based on facilitated discussion and consensus generation using a modified Delphi session. The recommendations were ratified with the expert panel. RESULTS: Facilitated discussion generated 31 issues within five themes, which were prioritized using expert voting. Consensus was achieved on the importance of short and simple treatment regimens for maximizing patient compliance, physician awareness of the progression of actinic keratosis to squamous cell carcinoma, provision of appropriate patient information, and the use of effective communication strategies to educate physicians about actinic keratosis. Based on these key findings, eight recommendations were generated. CONCLUSIONS: The recommendations will assist physicians when prescribing topical actinic keratosis therapy. Further research should focus on the types of patient outcomes that are influenced by the characteristics of topical field therapy.

Topical therapy is important in the treatment of actinic keratosis (AK), a major risk factor for, and early development stage of, squamous cell carcinoma. Despite this, research addressing the limitations and challenges associated with topical field therapy in actinic keratosis is lacking.

Background European guidelines for the management of basal cell carcinoma (BCC) prepared by the former BCC subcommittee of the Guidelines Committee of the European Dermatology Forum (EDF) were published in 2006. Objectives To present updated guidelines that include consensual expert definitions on various BCC types, prognosis and risk factors for BCC as well as review recommendations for diagnosis and treatment reflecting current published evidence. Methods These guidelines (S1 type) were prepared by the new BCC subgroup of the European Dermatology Forum (EDF)'s Guidelines Committee through extensive literature review (up to 2012) and expert experience; they were extensively discussed within the EDF subcommittee and approved by peer reviewers of the EDF. Results BCC is a common tumour with an incidence rising worldwide. Three major clinical types of BCC are recognized: nodular, superficial and morpheaform. Four histological subtypes are defined: superficial, nodular, infiltrative and morpheaform. On the basis of the risk of relapse, three prognosis groups have been identified: high, intermediate and low risk. According to these classifications and evidence-based evaluation of the therapeutic strategies available, a decision tree is proposed for the management of BCCs. Conclusions. The guidelines offer a useful tool that will help dermatologists to select the most appropriate treatment for individual patients.

Item does not contain fulltext, BACKGROUND: The incidence of actinic keratoses (AK) and non-melanoma skin cancer (NMSC) in organ transplant recipients (OTRs) is significantly higher than in immunocompetent patients. Rates of progression and recurrence following treatment are higher too, in part due to the effects of the immunosuppressant drugs. Conventional therapies for AK, using curettage, cryotherapy, surgical excision, topical therapies and photodynamic therapy (PDT), are often less effective, and may be inappropriate, for treating the greater numbers and extent of lesions in OTRs. Moreover, there are no specific protocols for treating this patient population that take into account the need for more frequent treatment and the increased pain associated with treating larger areas. OBJECTIVES: Recently, a pan-European group of dermatologists with expertise in this area met to share current best practice in PDT for the treatment of AK in OTRs. METHODS: The group identified areas where PDT currently is not meeting the needs of these patients and discussed how these gaps might be addressed. RESULTS/CONCLUSIONS: This position article summarizes those discussions and makes recommendations concerning a standardized protocol for treating OTRs, for a large randomized controlled trial to provide robust data on safety, efficacy and optimal pain control, and to provide pharmaco-economics data that can be used to support extended reimbursement in this patient group. The authors also recommend a second clinical trial to further investigate induced immunosuppression with PDT in healthy volunteers.