Title: Squamous cell carcinoma Prevention in Organ transplant recipients using Topical treatments (SPOT): a feasibility study
Funder: Department of Health and Social Care

Abstract: Background Cutaneous squamous cell carcinoma (cSCC) is numerically and economically a major burden to the NHS. The incidence is rising rapidly, with approximately 30,000 new cases per year in the UK. Immunosuppressed organ transplant recipients (OTR) have a more than 100-fold increased risk and an accelerated carcinogenic process, making them an ideal population in which to test interventions aimed at preventing cSCC. Premalignant lesions, termed actinic keratoses (AK), are present on sun-damaged skin and effective topical agents are available to treat them. The close relationship between AK and cSCC means that such topical treatment of a field bearing multiple AK should significantly reduce subsequent risk of developing cSCC, but this assumption has never been directly tested. Aims To establish the feasibility of a Phase III RCT evaluating prevention of cSCC using currently available topical interventions. Specific aims are: 1. To measure clearance of AK over a 3-month treatment period, and persistence of clearance over a 12-month post-treatment period in OTR. 2. To standardise methods for clinical identification and quantification of AK. 3. To address feasibility issues, eg tolerability of intervention, pertinent to study design for a Phase III RCT. 4. To address feasibility issues pertinent to design of a health economic component, e.g. testing the sensitivity of QoL instruments to measure change. 5. To develop a qualitative component examining patient preferences including design and piloting of discrete choice questionnaire. Plan of Investigation This will incorporate a randomised 3-arm parallel group comparison of field treatments for AK using 2 currently available topical therapies (5-fluorouracil cream or 5% imiquimod cream) plus sunscreen, versus a sunscreen-only control arm. Clearance of AK will serve as a surrogate for cSCC development, but actual event rate (of cSCC) and other feasibility issues relevant to a subsequent Phase III RCT will also be examined. Sixty patients, each with a minimum of 10 AK, will be randomised (1:1:1) into each of the 3 study arms in each centre. The 3-month treatment phase will include dose escalation to ensure best possible clearance of AK, and will be followed by 12-month post-treatment surveillance. A qualitative component will pilot discrete choice questionnaires. Potential Impact Skin cancers are often multiple and carry significant morbidity. SCC have visible precursor lesions (AK) present in 23% of the UK population over 60 years, providing an opportunity to identify high-risk individuals and prevent skin cancer by treating ‘fields’ of AK with currently available cream treatments. The Health Care cost of an SCC exceeds £1000 and complicated cases are far more expensive. Extrapolation from Australian sunscreen studies predicts a 40% reduction in SCC with active intervention. Even if shown to reduce the incidence of SCC by 10%, the financial and clinical benefit of this strategy would be substantial. The accelerated carcinogenesis seen in OTR makes them ideal to test this intervention, but a feasibility study is needed to inform final study design.

Lay abstract: Squamous cell carcinoma (SCC) is an exceedingly common skin cancer in the UK, with approximately 30,000 new cases each year. SCC rates are increasing rapidly and will continue to do so with our ageing and more sun-exposed population. Many people affected will develop multiple SCC, usually requiring repeated surgical procedures. These may be disfiguring, particularly as they occur on visible sun-exposed sites, such as the face. SCC also causes more than 20% of skin cancer-related deaths and is numerically and economically a major burden to the NHS. Actinic keratoses (AK) are common skin lesions, estimated to affect almost a quarter of the UK population over 60y. They are potentially precancerous lesions for SCC. Although only a fraction of individual AK progress to SCC, there is a close relationship between AK numbers and SCC risk. Therefore, in addition to sun avoidance, treatment of areas of skin bearing multiple AK may prevent development of SCC. Surprisingly, this possibility has never been properly tested. Organ transplant patients are an ideal patient group in whom to investigate this hypothesis as they have a very high (100-fold increased) risk of developing SCC and show an accelerated progression from AK to SCC. In this study, 60 transplant patients will be recruited into one of 3 groups; either one of 2 commonly used cream treatments for AK (5-fluorouracil or imiquimod) or a sunscreen-only control group. Creams will be applied over two 4-week treatment periods to clear any visible AK and participants will be monitored for a further 12 months. This small study will pave the way for the large trial needed to provide robust evidence that this treatment is a cost effective and acceptable way of preventing skin cancers. The potential health and cost benefits to the NHS of successful skin cancer prevention are enormous and we predict a successful outcome would see this treatment becoming an important tool in the fight against skin cancer.

Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CANCER AND NEOPLASMS