Title: A prospective 2 arm randomised controlled trial comparing the use of open label pentoxifylline and tocopherol versus current standard of care for the prevention of fibrosis related outcomes in irradiated head and neck oncology patients (Feasibility Study)
Funder: Department of Health and Social Care

Abstract: Background: Radiotherapy for head and neck cancer is an established treatment modality. Subsequently the treatment leads to post-radiotherapy effects of dysphagia, trismus and at its extreme osteoradionecrosis (ORN). These outcomes occur through the same process of radiation induced fibrosis (RIF). The effects are life long and progressive becoming more difficult to manage later in life. The consequence of these leads to poor function (eating, drinking, speech) and the eventuality of this has an effect on quality of life. The pathophysiology of RIF has been described in many other specialties such as breast cancer and has seen successful treatment through the use of pentoxifylline and vitamin E (PVe). The head and neck fraternity has taken the effects of this treatment on board and began using it to treat established ORN with success. Its prophylactic role however remains unknown. Aims: The larger aim is to determine whether the use of prophylactic PVe can reduce or even eliminate RIF outcomes. This trial will be a large RCT with a placebo arm. However, before such a commitment can be made to a large trial there remains some fundamental issues regarding whether a trial is possible. Hence the aim of this feasibility study is to investigate these unknown issues to aid the design of the substantive trial Question to be addressed: There are numerous questions that need addressing such as what will be the recruitment, retention and adherence rates? These are important to address and understand so that the substantive study can be powered appropriately and hence the required multiple centres needed can be invited. However, a further question remains regarding the formulation of the PVe. Patients will be asked to commence treatment immediately following completion of radiotherapy. At this stage the mouth is acutely inflamed and hence ingesting tablets may not be possible. It is also unknown when after radiotherapy patients can swallow tablets again. This information is fundamental to the study as compliance of the medication is paramount to able to investigate whether PVe can counteract RIF if taken prophylactically. It is this lack of information which is restricting a substantive trial and hence can only be obtained through a feasibility study such as this. Plans to investigate: The research group have designed a prospective 2 arm randomised controlled trial comparing the use of open label pentoxifylline and tocopherol versus current standard of care for the prevention of fibrosis related outcomes in irradiated head and neck oncology patients as feasibility study. Participants will be randomised in a 3:1 ratio (Treatment: standard care) to enable better assessment of patient preference for drug formulation. Follow up will be carried out by both clinical review as well as telephone. Participants will also undertake a series of questionnaires regarding swallowing difficulties and quality of life questionnaires and have mouth opening measurements taken. Potential benefits: The current trial design and approach will replicate the substantive trial so to allow areas of improvement to be identified. The information gained from this feasibility study will allow the research team to answer questions highlighted above. No substantial clinical data is likely to be produced from this study however without it a substantive trial cannot be planned and the associated clinical questions will remain unanswered.

Lay abstract: This research investigates unwanted side-effects of radiotherapy (RT) for the treatment of head and neck cancer. RT in this region causes swallowing difficulties and restricted mouth opening resulting in inadequate diet, impaired speech and poor oral hygiene. Further complications include osteo-radio-necrosis (ORN) - a condition where the jaw-bone becomes exposed and dies. This leads to pain, swelling and infection. Progression can cause jaw fractures. ORN is difficult to treat with no agreed standard treatment. Severe ORN requires very complex invasive surgery where large segment of the jaw is removed. A cure is not guaranteed and the recovery is often prolonged and fraught with complications. Currently there are no defined preventative measures to avoid ORN. The only semi-effective strategy is removal of numerous teeth (often healthy teeth) before RT?. These teeth may not be replaced in the future for fear of causing ORN. Recently, medications for improving blood circulation (pentoxifylline) in combination with vitamin E (PVe) have shown to cure ORN. This was first discovered treating radiation damage in breast cancer and the concept then applied to head and neck RT. With the effect ORN has on patient s quality of life it remains imperative to avoid it. A proposition is to give patients PVe immediately after RT to counteract radiation damage to normal tissue and avoid ORN, restricted mouth opening and swallowing problems. ? This study aims to examine the feasibility of undertaking a trial to compare the current best standards of care (BSC) at present versus BSC plus PVe in 68 participants assigned randomly for a 6month period. Reviews will include compliance and adherence of PVe medication, checking for ORN, mouth opening measurements, blood samples and completing questionnaires. This study will identify whether this trial is practical and acceptable to patients and clinicians on a larger scale.

Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS