John T. Lear

Evidence for field cancerisation treatment of actinic keratoses with topical diclofenac in hyaluronic acid

Actinic keratosis (AK) is a common skin disease seen in daily practice. It is associated with a risk of progression to invasive squamous cell carcinoma and can be regarded as a marker of increased risk for nonmelanoma skin cancer. The use of a field-directed treatment approach reflects the need to initiate early treatment over an affected area to prevent tumour development and local recurrence. Candidate field-directed treatments require a mechanism of action compatible with an effect on field cancerisation, immediate and long-term efficacy against visible lesions and efficacy against subclinical AK. Applicability to large treatment areas, tolerability compatible with long-term use, utility in organ transplant patients and, ideally, evidence of extended long-term activity may also be desirable. We review the evidence of a role for topical diclofenac sodium 3% administered in a 2.5% hyaluronic acid gel (diclofenac/HA) as field-directed treatment. Diclofenac/HA directly targets AK pathophysiology through multiple mechanisms, including induction of apoptosis, inhibition of angiogenesis and reduced inflammation. Clearance of visible field cancerisation is safely and rapidly achieved with a 90-day treatment course in patients with affected areas of up to 50 cm2 and is associated with a ≥75% reduction in target lesion number score in 85% and 91% of patients, respectively, at 30 days and 1 year post-treatment. Following treatment of AK in high-risk transplant patients, 45% remained free of lesions in the treatment area at 2 years post-treatment. We conclude that diclofenac/HA fulfils most criteria necessary to be considered an appropriate candidate for a field-directed treatment in AK.

Utilities for advanced basal cell carcinoma.

Abstract Objective: Most incidences of basal cell carcinoma are cured by a number of surgical or non-surgical treatments. However, a few patients have lesions which have metastasized or progressed to an extent that surgery or other treatment options are not possible. The lesions associated with advanced basal cell carcinoma (aBCC) can be disfiguring, affecting patients’ psychological state, general quality-of-life (QoL), and potentially life expectancy. The objective of this study was to capture societal utility values for health states related to aBCC, using the time trade-off (TTO) methodology. Methods: Nine health states were developed with input from expert clinicians and literature. States included: complete response (CR), post-surgical, partial response (PR) (with differing sized lesions [2 or 6u2009cm]), stable disease (SD) (with differing size and number of lesions [2 or 6u2009cm, or multiple 2u2009cm]) and progressive disease (PD) (with differing sized lesions [2 or 6u2009cm]). A representative sample of 100 members of the UK general public participated in the valuation exercise. The TTO method was used to derive utility values based upon subjects’ responses to decision scenarios; between living in the health state for 10 years or living in a state of full health for 10-x years. Results: Mean utility scores were calculated for each state. The least burdensome state as valued by subjects was CR (meanu2009=u20090.94; SDu2009=u20090.08), suggesting only a minimal impact on QoL. The state valued as having a greatest impact on QoL was PD, with a 6u2009cm lesion (meanu2009=u20090.67, SDu2009=u20090.25). Limitations and conclusions: Not all possible presentations of aBCC were included; the disease is a challenging condition to characterise given its rarity, the nature of the patients affected, and its variable progression. Findings suggest that aBCC is associated with significant burden for individuals, even when their disease is stable or where surgical treatment has been successful.

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.

Sequential Treatment of Multiple Actinic Keratoses with Solaraze and Actikerall

Interest is increasing in the use of sequential or combined therapeutic modalities for spot or area treatment of actinic keratoses (AKs) to achieve complete sustained remission. For multiple lesions in a contained area, topical treatment offers less discomfort, better cosmesis and greater patient convenience than destructive/ablative techniques. Twelve patients with multiple grade I and II AK lesions of the scalp (cases 1-10) or the dorsum of the hand (cases 11 and 12), most with a history of recurrence, were treated with Solaraze gel (3% diclofenac sodium in 2.5% hyaluronic acid) twice daily for 12 weeks, followed by a 2-week treatment-free interval, then Actikerall cutaneous solution (5-fluorouracil 5 mg/g and salicylic acid 100 mg/g) once daily for up to 6 weeks as required. Sequential treatment provided complete (clinical and histological) clearance in 8/10 male patients. Two patients with numerous lesions had partial clearance (significant improvement) and the remaining few lesions were treated with erbium laser. Both female patients achieved complete clinical clearance with sequential treatment. Solaraze/Actikerall were well tolerated. A case of contact dermatitis with Solaraze resolved after discontinuation and the patient progressed to treatment with Actikerall. Local application site reactions resolved upon treatment completion. Topical lesion-directed sequential treatment with Solaraze/Actikerall is a rational approach to treat patients with multiple AKs. Sequential treatment produces excellent clearance rates which are accompanied by relevant improvement in patients quality of life.

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

Abstract Objective: The objective of this analysis was to estimate the relative cost-effectiveness of Actikerall1 (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.

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

BackgroundUnderstanding 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.ObjectivesTo 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).Materials & methodsA 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.ResultsTreatment 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.ConclusionsThese 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.

1125PPATIENT-REPORTED QUALITY OF LIFE (QOL) WITH SONIDEGIB (LDE225) IN ADVANCED BASAL CELL CARCINOMA (BCC)

ABSTRACT Aim: Advanced BCC can cause considerable morbidity and severe disfigurement, leading to emotional and psychological distress and reduced QOL. The hedgehog (Hh) pathway is aberrantly activated in ≥ 95% of BCCs. Sonidegib blocks the Hh pathway by selective inhibition of smoothened. In a phase 2 study (BOLT; NCT01327053), patients (pts) with advanced BCC achieved meaningful disease control with sonidegib. The impact on pt-reported QOL is presented here. Methods: Pts with locally advanced BCC (LaBCC) not amenable to curative surgery or radiotherapy (n = 194) or metastatic BCC (mBCC; n = 36) were randomized to receive sonidegib 200 or 800u2003mg (1:2) once daily. QOL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the associated Head and Neck cancer module (HN and 11.1, 11.3, 5.6, and 16.5 months for physical functioning, social functioning, fatigue, and weight loss, respectively, and NE for other scales with 800u2003mg. Conclusions: Overall, pts treated with sonidegib in the BOLT trial maintained or improved their functioning and QOL, supporting the treatment effect observed in pts with advanced BCC and the favorable tolerability of sonidegib. Table. Pt-Reported QOL in Pts With Advanced BCC Treated With Sonidegib. Pts Na n (%)b Sonidegib 200u2003mg once daily Sonidegib 800u2003mg once daily LaBCC mBCC LaBCC MBCC EORTC QLQ-C30 Physical functioning N = 61 N = 13 N = 110 N = 20 Improvement from BL 22 (36.1) 9 (69.2) 35 (31.8) 8 (40.0) No change from BL 29 (47.5) 3 (23.1) 38 (34.5) 10 (50.0) Social functioning N = 61 N = 13 N = 109 N = 20 Improvement from BL 16 (26.2) 5 (38.5) 22 (20.2) 7 (35.0) No change from BL 40 (65.6) 6 (46.2) 75 (68.8) 12 (60.0) Pain N = 61 N = 13 N = 110 N = 20 Improvement from BL 19 (31.1) 6 (46.2) 36 (32.7) 11 (55.0) No change from BL 36 (59.0) 7 (53.8) 52 (47.3) 7 (35.0) Fatigue N = 61 N = 13 N = 109 N = 20 Improvement from BL 23 (37.7) 6 (46.2) 21 (19.3) 8 (40.0) No change from BL 26 (42.6) 6 (46.2) 55 (50.5) 8 (40.0) EORTC HN R. Gutzmer: has served an advisory role for Roche, MSD, BMS, Novartis (NVS), GSK; received honoraria from Roche, BMS, MSD, Janssen, Amgen, GSK, Almirall, NVS, MerckSerono, Pfizer; and received research funding from Roche, NVS, Pfizer; M.R. Migden: has served an advisory role and received honoraria from Genentech, Novartis, Lilly; received institutional research funding from Genentech; provided expert testimony on behalf of Novartis; K. Higuchi: Keiko Higuchi is employed by Novartis; S. Gogov: is employed by Novartis and owns stock; T. Yi: Dr. Tingting Yi is employed by Novartis and owns stock; R. Herd: has received research funding from Novartis; R. Kudchadkar: has served an advisory role and received honoraria from Genentech and BMS; U. Trefzer: has served an advisory role and received honoraria from Roche; J. Lear: has received honoraria from Novartis; D. Sellami: is employed by Novartis and owns stock; A. Guminski: has served an advisory role for Novartis. All other authors have declared no conflicts of interest.