Pharmacokinetics and pharmacodynamics of Hedgehog pathway inhibitors used in the treatment of advanced or treatment-refractory basal cell carcinoma.

INTRODUCTION: Sonidegib and vismodegib are currently the only US Food and Drug Administration and European Medicines Agency-approved small-molecule Hedgehog pathway inhibitors (HHIs)for treating adults with advanced or refractory basal cell carcinoma (BCC) that is not amenable to conventional surgery or radiotherapy. At this time, there are no head-to-head clinical trials comparing these two HHIs for efficacy and safety to assist clinicians with determining which HHI may be best suited for their patients. AREAS COVERED: This review briefly describes the pathogenesis of BCC, provides a detailed overview of the key pharmacokinetic profile differences between sonidegib and vismodegib, explains their pharmacodynamics, and highlights the therapeutic considerations when either HHI is used to treat special patient populations. EXPERT OPINION: Although both HHIs act at the same molecular target in the Hedgehog pathway, there are significant differences in their pharmacokinetic profiles that may play a potential role in their efficacy and safety. Evidence-based recommendations serve to inform clinicians until direct comparative clinical trials of sonidegib versus vismodegib are conducted to determine the clinical relevance of the reported differences in their pharmacokinetic properties.

Concomitant medication use does not appear to alter long-term efficacy of sonidegib for advanced basal cell carcinoma: a post hoc analysis based on the 42-month BOLT study.

BACKGROUND: Sonidegib is approved to treat locally advanced basal cell carcinoma (laBCC) in patients not amenable to surgery or radiation. The BOLT trial demonstrated durable efficacy of sonidegib in laBCC patients over 42 months. BCC is most common in the elderly, who often take chronic medications. OBJECTIVES: We evaluated the efficacy of sonidegib (200 mg daily) in laBCC patients on select concomitant medications. MATERIALS & METHODS: In the Phase II BOLT study, laBCC patients were randomized 1:2 to sonidegib 200 mg:800 mg daily. The primary endpoint was objective response rate (ORR) per central review. Post hoc assessments included ORR and duration of response (DOR) per investigator review for patients on concomitant medications. RESULTS: At 42 months, ORR for laBCC patients taking sonidegib 200 mg daily (n=66) was 71.2% and DOR was 15.7 months according to investigator review. Patients on select concomitant medications (n=37) had an ORR of 73.0%; DOR was not estimable. CONCLUSION: Administration of sonidegib with concomitant medications, excluding strong cytochrome P450 3A4/5 inhibitors/inducers, does not appear to alter its efficacy in laBCC patients.

Germline intergenic duplications at Xq26.1 underlie Bazex-Dupré-Christol basal cell carcinoma susceptibility syndrome.

BACKGROUND: Bazex-Dupré-Christol syndrome (BDCS; MIM301845) is a rare X-linked dominant genodermatosis characterized by follicular atrophoderma, congenital hypotrichosis and multiple basal cell carcinomas (BCCs). Previous studies have linked BDCS to an 11·4-Mb interval on chromosome Xq25-q27.1. However, the genetic mechanism of BDCS remains an open question. OBJECTIVES: To investigate the genetic aetiology and molecular mechanisms underlying BDCS. METHODS: We ascertained multiple individuals from eight unrelated families affected with BDCS (F1-F8). Whole-exome (F1 and F2) and genome sequencing (F3) were performed to identify putative disease-causing variants within the linkage region. Array comparative genomic hybridization and quantitative polymerase chain reaction (PCR) were used to explore copy number variations, followed by long-range gap PCR and Sanger sequencing to amplify the duplication junctions and to define the head-tail junctions. Hi-C was performed on dermal fibroblasts from two affected individuals with BDCS and one control. Public datasets and tools were used to identify regulatory elements and transcription factor binding sites within the minimal duplicated region. Immunofluorescence was performed in hair follicles, BCCs and trichoepitheliomas from patients with BDCS and sporadic BCCs. The ACTRT1 variant c.547dup (p.Met183Asnfs*17), previously proposed to cause BDCS, was evaluated with t allele frequency calculator. RESULTS: In eight families with BDCS, we identified overlapping 18-135-kb duplications (six inherited and two de novo) at Xq26.1, flanked by ARHGAP36 and IGSF1. Hi-C showed that the duplications did not affect the topologically associated domain, but may alter the interactions between flanking genes and putative enhancers located in the minimal duplicated region. We detected ARHGAP36 expression near the control hair follicular stem cell compartment, and found increased ARHGAP36 levels in hair follicles in telogen, in BCCs and in trichoepitheliomas from patients with BDCS. ARHGAP36 was also detected in sporadic BCCs from individuals without BDCS. Our modelling showed the predicted maximum tolerated minor allele frequency of ACTRT1 variants in control populations to be orders of magnitude higher than expected for a high-penetrant ultra-rare disorder, suggesting loss of function of ACTRT1 variants to be an unlikely cause for BDCS. CONCLUSIONS: Noncoding Xq26.1 duplications cause BDCS. The BDCS duplications most likely lead to dysregulation of ARHGAP36. ARHGAP36 is a potential therapeutic target for both inherited and sporadic BCCs. What is already known about this topic? Bazex-Dupré-Christol syndrome (BDCS) is a rare X-linked basal cell carcinoma susceptibility syndrome linked to an 11·4-Mb interval on chromosome Xq25-q27.1. Loss-of-function variants in ACTRT1 and its regulatory elements were suggested to cause BDCS. What does this study add? BDCS is caused by small tandem noncoding intergenic duplications at chromosome Xq26.1. The Xq26.1 BDCS duplications likely dysregulate ARHGAP36, the flanking centromeric gene. ACTRT1 loss-of-function variants are unlikely to cause BDCS. What is the translational message? This study provides the basis for accurate genetic testing for BDCS, which will aid precise diagnosis and appropriate surveillance and clinical management. ARHGAP36 may be a novel therapeutic target for all forms of sporadic basal cell carcinomas.

Clinicopathological characteristics of individuals with coexisting melanoma and chronic lymphocytic leukaemia: a multicentre cohort study.

BACKGROUND: Individuals with a prior diagnosis of chronic lymphocytic leukaemia (CLL) have a higher risk of developing melanoma and exhibit poorer outcomes than patients without CLL. However, there are limited data reporting the clinicopathological features of melanoma diagnosed in patients with CLL. AIMS: To review clinicopathological characteristics of patients with coexisting diagnoses of melanoma and CLL. METHODS: A retrospective review was undertaken for patients with coexisting diagnoses of melanoma and CLL between 2005 and 2015 in 11 centres in the UK and Ireland. RESULTS: Overall, 46 cutaneous melanomas identified in 45 patients were included. In 28 (62.2%) patients, melanoma was diagnosed after an existing diagnosis of CLL. In this group, mean Breslow thickness was 2.7 mm (range 0.2-25 mm). Ten patients (35.7%) developed locoregional recurrence and 8 (28.6%) developed distant metastases. Melanoma-specific mortality was 5 of 28 (17.9%) and all-cause mortality was 13 of 28 (46.4%). In 17 patients, melanoma was diagnosed before CLL. In this group, mean BT was 2.9 mm (range 0.4-14 mm); five patients (29.4%) developed locoregional recurrence and three (17.6%) developed distant metastases. Melanoma-specific mortality was 1 of 17 (5.8%) and all-cause mortality was 5 of 17 (29.4%) in this group. CONCLUSIONS: To our knowledge, this is the first and largest cohort study to report clinicopathological data of coexisting melanoma and CLL in the UK and Ireland. Although the thickness of primary melanoma was not different before or after a CLL diagnosis, melanoma recurrence and melanoma-specific mortality appear to be more common in patients with a prior diagnosis of CLL.

A Real-World Data Study on the Healthcare Resource Use for Uncontrolled Moderate-to-Severe Atopic Dermatitis in Secondary Care in the United Kingdom Prior to the Introduction of Biologic Treatment.

Background: Whilst there is international evidence around the high healthcare resource utilization (HRU) associated with atopic dermatitis (AD), there is a lack of published data from the United Kingdom (UK). Methods: A retrospective, descriptive, observational study was conducted to evaluate the burden of moderate-to-severe AD on the National Health Service (NHS) in an adult UK population treated with traditional standard of care prior to the introduction of biologics. Patients (n=59) were recruited from 6 UK NHS Hospital Trusts and observed over three years. Results: 707 dermatology clinic visits were recorded over the observation period, amounting to 6.6 visits per patient-year, most commonly for routine check-ups most of which involved dermatology consultants (n=469, 66%). Physicians were the most consulted healthcare professional (n=652, 92%); emollients were the most common treatment (n=80 courses). 174 flares requiring additional medical advice were recorded in total (1.6 per patient-year). Discussion/Conclusions: Complex treatment pathways for adult patients in the UK with moderate-to-severe AD incur considerable HRU, particularly for those patients non-responsive to systemic therapies with broad immunosuppressant action. Recent advances in biologics-based AD management could possibly have a significant positive impact on HRU through significant reduction in the number of NHS touch points identified in this study.

Comparison of ALitretinoin with PUVA as the first-line treatment in patients with severe chronic HAnd eczema (ALPHA): study protocol for a randomised controlled trial.

INTRODUCTION: Hand eczema (HE) is one of the most common skin disorders and an important cause for morbidity and occupational disability. The 1-year prevalence of HE is estimated to be up to 10% and it is estimated that 5%-7% of those develop severe chronic HE. However, current clinical evidence is not compelling enough to guide clinical practice. In a survey among 194 UK dermatologists the most frequent first choice approaches were psoralen combined with ultraviolet A (UVA) treatment (PUVA), oral steroids and alitretinoin (AL). When asked which strategy was most efficient for long-term outcome 20% of clinicians indicated they did not know; 43% of clinicians reported AL and 30% reported PUVA. METHODS AND ANALYSIS: ALPHA is a multicentre, open, prospective, two-arm parallel group, randomised controlled trial comparing PUVA and AL with a planned sample size re-estimation. Between 500 and 780 participants will be randomised on a 1:1 basis. The physician's global assessment (PGA) will direct treatment after randomisation, non-responders will be treated according to usual clinical practice; providing valuable pilot data on second line therapeutic approaches to inform future trials.Assessments will be conducted up to 52 weeks post randomisation. The primary outcome measure is the Hand Eczema Severity Index at 12 weeks. Secondary outcome measures include modified Total Lesion Symptom Score, PGA, time to relapse, patient reported outcome measures and DNA extraction and assessment of genetic variants. A substudy on molecular inflammatory mediators will provide information on subgroup specific treatment responses. Photographs will be taken and HE severity assessed by a central review panel. ETHICS AND DISSEMINATION: Ethics approval was obtained from Leeds West Research Ethics Committee (14/YH/1259).Trial results will be disseminated at relevant clinical conferences and societies, published in peer-reviewed journals and through relevant patient groups. TRIAL REGISTRATION NUMBER: ISRCTN80206075.

Topical treatment of actinic keratoses in organ transplant recipients: a feasibility study for SPOT (Squamous cell carcinoma Prevention in Organ transplant recipients using Topical treatments).

BACKGROUND: The risk of cutaneous squamous cell carcinoma (cSCC) is significantly increased in organ transplant recipients (OTRs). Clearance of actinic keratoses (AKs) is generally regarded as a surrogate biomarker for cSCC prevention. OTR-cSCC chemoprevention with topical AK treatments has not been investigated in randomized controlled trials (RCTs), although there is evidence that 5% 5-fluorouracil (5-FU) may be chemoprotective in immunocompetent patients. OBJECTIVES: To assess the feasibility, activity and evaluation outcomes relevant to the design of a future phase III RCT of topical cSCC chemoprevention in OTRs. METHODS: OTRs with 10 or more AKs in predefined areas were randomized 1 : 1 : 1 to topical 5-FU, 5% imiquimod (IMIQ) or sunscreen (sun-protective factor 30+) in a phase II, open-label RCT over 15 months. Feasibility outcomes included proportions of eligible OTRs randomized, completing treatment and willing to be re-treated. AK activity [AK clearance, new AK development, patient-centred outcomes (toxicity, health-related quality of life, HRQoL)] and evaluation methodology (clinical vs. photographic) were assessed. RESULTS: Forty OTRs with 903 AKs were randomized. All feasibility outcomes were met (56% of eligible OTRs were randomized; 89% completed treatment; 81% were willing to be re-treated). AK activity analyses found 5-FU and IMIQ were superior to sunscreen for AK clearance and prevention of new AKs. 5-FU was more effective than IMIQ in AK clearance and prevention in exploratory analyses. Although toxicity was greater with 5-FU, HRQoL outcomes were similar. CONCLUSIONS: Trials of topical AK treatments in OTRs for cSCC chemoprevention are feasible and AK activity results support further investigation of 5-FU-based treatments in future phase III trials. What is already known about this topic? Cutaneous squamous cell carcinoma (cSCC) is significantly more common in immunocompromised individuals including organ transplant recipients (OTRs) compared with immunocompetent populations. cSCC chemoprevention activity of sunscreen and 5-fluorouracil-based (5-FU) actinic keratosis (AK) treatments has been demonstrated in randomized controlled trials (RCTs) in immunocompetent populations but not in OTRs. AKs are cSCC precursors and their clearance and prevention are generally regarded as surrogate endpoint biomarkers for potential cSCC chemoprevention activity. What does this study add? SPOT (SCC Prevention in OTRs using Topical treatments) has confirmed that RCTs of OTR-cSCC chemoprevention with topical AK treatments are feasible. It also suggests that topical 5-FU may be superior to 5% imiquimod and sunscreen in AK clearance and prevention. Together with recent evidence from several RCTs in the general population, these data provide a compelling rationale for further studies of intervention with 5-FU-based topical chemoprevention approaches in OTR-cSCC prevention.

Using drug scheduling to manage adverse events associated with hedgehog pathway inhibitors for basal cell carcinoma.

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.

Emerging trends in the treatment of advanced basal cell carcinoma.

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.

Treatment patterns and outcomes for patients with locally advanced basal cell carcinoma before availability of Hedgehog pathway inhibitors: a retrospective chart review.

Understanding the molecular basis of basal cell carcinoma (BCC) has led to development of Hedgehog pathway inhibitors (HPIs) for patients with advanced forms of BCC (aBCC). A practical definition of aBCC as a distinct disease entity is unavailable, and epidemiological information is limited. To conduct the RONNIE study to describe characteristics, treatment patterns, and outcomes of patients with aBCC during the period preceding HPI introduction, as well as results from patients with locally advanced BCC (laBCC). A retrospective chart review was conducted using data from adult patients with a new diagnosis of laBCC between 1st January 2005 and 31st December 2010. The study period was 1st January 2005 to 31st December 2011 to allow for inclusion of at least 12 months of follow-up information for all patients. RESULTS: Treatment data were available for 106/117 patients. Radiation and excisional surgery were the most common first-line treatment options (43.4% and 23.5% of patients, respectively). Patients typically received multiple subsequent treatments; no apparent trend or pattern was observed. Complete visual response, partial visual response, and stable disease were obtained in 51.9%, 25.9%, and 11.1% of patients, respectively, after first-line surgery, and in 53.7%, 22.0%, and 9.8%, respectively, after first-line radiation. Median progression-free survival after first-line treatment was 32.1 months. Median overall survival was 78.8 months. These data represent a baseline for laBCC before HPIs became part of the treatment algorithm. The observed heterogeneity of treatment patterns highlights the lack of an established standard treatment for laBCC before HPIs were available.

Vismodegib for Locally Advanced Periocular and Orbital Basal Cell Carcinoma: A Review of 15 Consecutive Cases.

Basal cell carcinoma (BCC) is the most common periocular skin cancer and can lead to significant morbidity. We assess the effectiveness of vismodegib, a first-in-class Hedgehog signaling pathway inhibitor, in the management of periocular and orbital BCCs based on clinical response, tolerability, and orbital content preservation. All patients with periocular or orbital BCCs who met criteria for vismodegib treatment were recruited prospectively between May 2012 and 2014 from 2 hospitals. Patients received oral vismodegib (150 mg daily) until disease progression, unacceptable toxicity, or withdrawal. All patients were followed up monthly. Patient demographics, tumor size, treatment duration including dosing regimen, adverse events, response rate, duration of response, progression-free survival, and disease-free survival were analyzed. All 15 patients had biopsy-proven BCCs with no metastatic disease at presentation. The mean age was 74 years and 10 patients (67%) had orbital involvement. The mean lesion longest dimension was 51 mm and 7 cases (47%) represented recurrence following previous surgery and/or radiotherapy. The mean treatment duration was 13 months and mean follow-up duration 36 months. Ten patients (67%) had a complete response, 3 (20%) had a partial response, and 2 had progressive disease following an initial partial response (13%). The partial response of 55% in 1 patient allowed subsequent surgical resection with clear margins. Vismodegib is effective for treating periocular and orbital BCCs with orbital salvage of patients who otherwise would have required exenteration. There is a neoadjuvant role for vismodegib but further studies are required.

First evidence of genotype-phenotype correlations in Gorlin syndrome.

BACKGROUND: Gorlin syndrome (GS) is an autosomal dominant syndrome characterised by multiple basal cell carcinomas (BCCs) and an increased risk of jaw cysts and early childhood medulloblastoma. Heterozygous germline variants in PTCH1 and SUFU encoding components of the Sonic hedgehog pathway explain the majority of cases. Here, we aimed to delineate genotype-phenotype correlations in GS. METHODS: We assessed genetic and phenotypic data for 182 individuals meeting the diagnostic criteria for GS (median age: 47.1; IQR: 31.1-61.1). A total of 126 patients had a heterozygous pathogenic variant, 9 had SUFU pathogenic variants and 46 had no identified mutation. RESULTS: Patients with variants were more likely to be diagnosed earlier (p=0.02), have jaw cysts (p=0.002) and have bifid ribs (p=0.003) or any skeletal abnormality (p=0.003) than patients with no identified mutation. Patients with a missense variant in PTCH1 were diagnosed later (p=0.03) and were less likely to develop at least 10 BCCs and jaw cysts than those with other pathogenic PTCH1 variants (p=0.03). Patients with SUFU pathogenic variants were significantly more likely than those with PTCH1 pathogenic variants to develop a medulloblastoma (p=0.009), a meningioma (p=0.02) or an ovarian fibroma (p=0.015), but were less likely to develop a jaw cyst (p=0.0004). CONCLUSION: We propose that the clinical heterogeneity of GS can in part be explained by the underlying or SUFU variant.

A Novel Actinic Keratosis Field Assessment Scale for Grading Actinic Keratosis Disease Severity.

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.

Managing adverse events associated with vismodegib in the treatment of basal cell carcinoma.

Basal cell carcinomas are the most common form of skin cancer. Some develop into advanced cases not suitable for standard therapy. Vismodegib is the first-in-class oral hedgehog pathway inhibitor (which is dysregulated in 90% of basal cell carcinomas), and has demonstrated efficacy for advanced disease in clinical trials. An UK expert panel met to discuss management strategies for adverse events associated with vismodegib (most commonly taste disturbances, muscle cramps and alopecia). Managing patient expectations and implementing treatment breaks were considered important strategies. Quinine was useful to alleviate muscle cramps. For taste disturbances, food swaps alongside dietician referral were suggested. The experts concluded that these common adverse events can be successfully managed to allow optimum treatment duration of vismodegib.

The cost-effectiveness of 5-FU-SA in the treatment of actinic keratoses of the face and scalp in the UK secondary care setting.

OBJECTIVE: The objective of this analysis was to estimate the relative cost-effectiveness of Actikerall 1 (5-FU-SA) vs cryotherapy in a secondary care setting in the UK, for lesion-directed treatment in patients with actinic keratoses (AK) of the face and scalp. METHODS: The model was a simple decision tree, with a 6-month time horizon. The perspective was that of the UK National Health Service (NHS). Modeled treatment effects included reported per-patient histological clearance and recurrence rates. Cost inputs comprised professional consultation time and cost of medication. Health-related utility estimation followed previously published methodology. Adverse events were not modeled. The key data and model structural assumptions followed expected UK practice. One-way and probabilistic sensitivity analyses were conducted to assess structural and parameter uncertainty. RESULTS: 5-FU-SA was found to be less costly (-£204) and more effective (+0.001 QALY) in base case and sensitivity analyses. In the probabilistic analysis there was 100% probability of being cost-effective over cryotherapy at £20,000 willingness to pay. Cost of professional time was a key driver of the model outcome. 5-FU-SA remained dominant across a range of scenario analyses, including exploration of assumptions around setting of care. LIMITATIONS: The time horizon of the analysis was short and data were not extrapolated beyond the duration of the clinical trial; however, this approach is consistent with likely follow-up of an AK patient. The clinical outcomes observed in the trial were based on a large proportion of cryotherapy patients undergoing an additional cycle of treatment; this may not occur or be required in an experienced secondary care setting. CONCLUSION: 5-FU-SA could be considered as a cost-effective choice for treatment of AK lesions of the face and scalp in secondary and mixed care settings in the UK. Use of 5-FU-SA in patients who would otherwise be managed with cryotherapy has the potential to result in cost savings.

Photodynamic Therapy and Non-Melanoma Skin Cancer.

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.