Award Title: 14/150 (12/205 Very Rare Diseases project number 112195): A randomised trial comparing surgical and radiotherapy strategies enabling rational treatment selection for primary Merkel Cell Carcinoma (MCC), a rare virus and immune-related aggressive skin cancer
Funder: Medical Research Council

Abstract: Merkel cell carcinoma (MCC) is rare but greatly impacts on patients. It starts on skin (the primary), grows fast and often spreads to nearby lymph nodes in the neck, armpit or groin. Spread to other organs is usually fatal. It must be treated effectively or it rapidly regrows. MCC can be treated by surgery and is very sensitive to radiotherapy (RT). _x000D_
We aim to compare treatments for the primary, something not done before. Most specialists remove the primary surgically with 1-3cm of apparently normal skin to reduce the chance of leaving behind satellite tumours. Sometimes RT is used after healing to kill residual cancer. RT can also control MCC if used earlier without prior extensive surgery. Prioritising RT as first treatment may be as effective as or better than prioritising surgery for disease control. _x000D_
This is an 8-year trial for people with primary MCC for whom either surgery or RT are feasible for disease control. It compares these two strategies in preventing cancer regrowth between and including the primary site and the nearby lymph nodes. Patients will be recruited over 5-years by specialist teams across the UK, with informed consent and all getting active treatment. Assessments will be for 2 years: not many MCC recur later. The treatments’ effect on well-being and resource use will be measured. Additional NHS costs will be for the informed consent process, quality control, data and tissue collection and PET scans, but not for treatments as all patients should be treated anyway. Five years recruitment should result sufficiently robust evidence to inform patients and clinicians deciding between treatments. _x000D_
Over the first 3 years, we will invite all new patients with MCC to give data, blood and tumour samples. Many or most will also enter the trial. This wider data collection makes efficient use of resource when studying a rare cancer. Some specialist centres might start recruiting for this wider study while they sort out their treatment pathways for the trial. At 3-years we will have data about the patients (e.g. age, sex, other illnesses), their treatment and a set of biological markers. The markers cover their immunity (whether they have had an illness or treatment suppressing immunity, measurement of white cells called lymphocytes in blood, standard measurements of how lymphocytes work), the cancer’s invasiveness and whether their cancer has been invaded by killer lymphocytes. _x000D_
At 3-years, we will ask if enough people are entering the trial and if it is likely that the trial will deliver a clear comparison between two different treatments, thus benefiting future patients. If not, the trial will close and high quality data about patients, their treatments and the biological markers will be analysed for a relationship to outcomes. If the feasibility phase shows that continuing the trial promises success, the trial will go on to complete 5-years recruitment. We will investigate which of prioritising either radiotherapy versus surgery to treat primary MCC is probably the more effective. We will also explore whether the biological markers of immunity and invasiveness predict the outcome of radiotherapy differently to the outcome of surgery. _x000D_
This project links specialist clinical teams nationwide, is led by a unit experienced in cancer trials for rare populations and uses a tissue bank competent to collect tissue specimens linked to accredited pathology and clinical immunology laboratories to measure the biological markers.

Lay Abstract: MCC is a rare skin cancer (200-300 cases across the UK annually) of older people, is locally invasive and has high metastatic potential. A paucity of trials means current treatments may be sub-optimal and their selection for individual patients not evidence-based. MCC cells carry integrated Merkel cell polyoma virus (MCPyV). Viral proteins may contribute to oncogenesis and be targets for immunity. Incidence of MCC is higher in immune suppressed states. Infiltration into tumour nodules of CD8+ cytotoxic T cells in MCC specimens associates with better outcome. Radiotherapy (RT) might affect immunity against MCC differently to surgery by exposing antigen presenting cells to immunogenic debris. For a rare cancer currently managed along diverse pathways, it is efficient to build a randomised trial addressing a single aspect of clinical decision-making, set within a wider registration study to maximise collection of clinical data and tissue for translational research, and with a feasibility phase to ensure the trial sits appropriately within real-life clinical pathways. _x000D_
In the UK, management is centred on skin specialist multidisciplinary teams (SSMDT). MCC is sensitive to RT. Many SSMDT treat primary MCC with WLE, sometimes with delayed local RT following graft healing. Earlier use of RT, following biopsy or a limited excision, might result in better local disease control. _x000D_
This is a UK-wide, multi-centre study over 8 years (5 years accrual), for patients with primary MCC considered for radical treatment to achieve durable loco-regional control. Treatment arms are (A) WLE, permitting subsequent adjuvant RT versus (B) prioritising early use of RT for primary MCC following local biopsy or excision but without prior WLE. The primary outcome measurement is time to loco-regional progression. QOL is a key secondary outcome measurement. The sample size derives from probability distributions for correctly identifying the better arm based on an event rate of 20% whereas the trial is not powered to confidently detect a difference between the arms with 5% significance. For example, an observed HR of 0.8 favouring arm A offers a 50% chance that arm A is clearly better than arm B (HR<0.8) and a 92 % chance arm A is roughly equivalent to or better than arm B (HR <1.2). Such data are more informative than current uncontrolled studies for individual decision-making. _x000D_
A critical component is the initial 3-year randomised feasibility study, embedded within registration of all consenting patients newly presenting with MCC, including those not randomised into the trial. This provides a tissue and data bank for future research coordinated by a licensed biorepository linked to CPA-accredited pathology and molecular laboratories. Recognised pathological biomarkers in MCC i.e. tumour viral status and intra-tumoural infiltration by cytotoxic T cells plus standard clinical markers of immune status will be analysed for a relationship with outcome. If the feasibility phase of the trial demonstrates sufficient accrual, and a high probability that the trial will deliver a meaningful comparison between two different treatments, the trial will continue to complete 5-years accrual, with ongoing tissue collection, and a further two years follow up. In that event, data from the feasibility/registration phase will be used to design further analysis of trial patients seeking interaction between immune markers measured at baseline, the randomised treatments and outcome.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.4 SURGERY;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health Categories: CANCER AND NEOPLASMS