Title: LiTEFORM. Lite Therapy Effectiveness For ORal Mucositis Trial. A randomised controlled trial of the clinical and cost effectiveness of Low Level Laser in the management of Oral Mucositis in Head and Neck cancer irradiation
Funder: Department of Health and Social Care

Abstract: A multi-centre (10 regional cancer centres in England and Wales) 2 arm, triple blinded randomised controlled trial to evaluate the effectiveness and efficiency of low level laser therapy (LLLT) in reducing the incidence of severe oral mucositis (OM) in adult patients receiving radiotherapy or chemoradiotherapy ((C)RT) for head and neck cancer (HNC). 380 adult patients starting (C)RT for HNC will be randomised on a 1:1 basis to: LLLT (n=190) or sham LLLT (n=190). Inclusion: Planned irradiation of 60 Gy or more to a CTV in the oral cavity or oropharynx for histologically proven HNC. Exclusion: parotid tumours, previous HNC, pre-existing OM & trismus. LLLT sessions 3 times weekly from day 1 of(C)RT. Laser parameters: 660nm, 50mW 1cm2 spot size, dose: 3J/spot (approx. 20 sites). Treatment would continue until resolution. LLLT delivered shortly before or after (C)RT sessions by nurses or allied healthcare professionals (AHPs). All patients included will receive the usual mouth-care offered for OM by each centre. Evidence suggests that there is little benefit from any of these. Primary outcome measure: difference in the OMWQ-HN at week 6. Secondary outcomes: weekly WHO mucositis scores; days of feeding tube use, admission, interruptions; weight. Quality of life (EORTC QLQ C30/HNC 35/EQ-5D 5L) at baseline, week 6, months 4 and 14, MDA dysphagia inventory at baseline, months 4 and 14, normalcy of diet weekly at weeks 1-6, months 4 and 14 months, timed water swallow at baseline, months 4 and 14. Safety (survival, recurrent/persistent disease at 14 months). Cost, quality adjusted life years (QALY), incremental cost per OM episode avoided and incremental cost per QALY over 14 months. For the economic evaluation costs will include the cost of LLLT and subsequent use of services vs standard care. Cost perspective will be NHS and personal and social services to participants and families. Unit costs will be derived from routine data sources (20) and study specific estimates. Discounting will be performed (NICE methods). QALYs will be estimated from EQ-5D responses. Deterministic and stochastic sensitivity analysis will be used. A qualitative process evaluation on: barriers and facilitators to recruitment and provision of LLLT at sites; patients’ and clinicians’ experiences of LLLT; and fit of LLLT within care pathways. It will involve interviews with a purposive sample of patients (n=40) and clinicians (n=40) from sites, over the set-up, patient recruitment and follow-up phases. Based on 190 patients in each trial arm and assuming a maximum of 20% drop-out or missing data, there would be 90% power to detect a 4-point difference between trial arms in the primary outcome measure, i.e. OMWQ-HN score at 6 weeks following randomisation, assuming a standard deviation of 10.7 (as in Epstein 2007) and based on a 2-sided test at the 5% level. This sample size was calculated using the power two means option in Stata (version 13.1). According to Epstein 2007, a group difference of 4 points would reflect a meaningful treatment effect. Recruitment over 24 months (9months pilot 100 patients, 15months full trial 280 patients): 2 patients/month/site. 1/4 of the eligible patients (audit data and a survey).Two pilots suggest this is realistic. Completion at 47 months. The members of the team have an established pedigree of delivering collaborative research work and innovation. The team is from a diverse background including a HNC survivor, clinicians, health economists, social scientists, statisticians and trialists.

Lay abstract: Pain and inflammation of the mouth (known as oral mucositis) is a common side effect of radiotherapy or chemo-radiotherapy for head and neck cancer and can last for several weeks after treatment has been completed. Approximately 4 out of 10 people will experience severe mucositis during their treatment, characterised by significant levels of pain, and inability to swallow. This can result in significant weight loss and also prolongs the side effects of the treatment as healing is delayed while the body is in a weakened state. Patients then require feeding via a feeding tube either inserted through the nose or directly into the stomach. To commence feeding and to control pain, patients require hospital admission for several days. Patients often struggle to cope with the effects of severe mucositis both due to the pain, but also because this complication leads to distress and isolation as people often do not want to be seen in public with a feeding tube in place. Occasionally the radiotherapy treatment is interrupted due to patients not feeling well enough to attend the centre, which can affect the long term control of the cancer. There is also a risk that mouth ulcers in severe mucositis can become infected with bacteria. The infection can spread to the blood, then on to other organs. This is known as sepsis and can be life-threatening. Current care (improved oral hygiene, mouthwashes, and special gels to coat the mouth) has limited impact on either preventing or treating this condition. Early studies have shown that low power laser light therapy can be used to prevent and treat mucositis by reducing its severity and shortening its duration. A thorough analysis of all available evidence has indicated the need for a larger and well conducted study to confirm these effects. The aim of this research is to compare laser treatment to fake laser treatment to see if the laser is really helping. Laser treatments last 20-30 minutes and would be given shortly before or after radiotherapy. The laser treatment is delivered by a small hand held device. The laser doesn't hurt or heat up the tissues, but it can harm the eyes and so protective eye shields are worn. Design: patients will be randomly allocated on a 1:1 basis to receive either laser treatment or sham laser treatment. Sham or real treatments would take place 3 times weekly. The effectiveness of laser treatment will be assessed by several methods. Patients will complete a short questionnaire on a weekly basis. We will also measure the extent of patients' mouth inflammation using a standard scoring system. We'll measure their ability to swallow water and eat a normal diet. We'll measure their quality of life using validated questionnaires. The use of health services and costs to them and their families will be recorded. These outcomes will allow us to compare the two groups accurately, looking to see if the laser improves the symptoms that patients experience and represents a good use of NHS funds. We have developed this study with the help of our active head and neck cancer patient and carer engagement group. A member of this group has joined the team as a co-applicant and will support our ongoing liaison with this wider group throughout the study. The results of the study will be shared through local and national conferences and peer reviewed journals, via patient groups and organisations, and through relevant clinical networks.

Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS;ORAL AND GASTROINTESTINAL