Title: PentoxIfylline and Tocopherol for the treatment of poST radiotherapy fibrOsis in head and neck cancer Patients: a feasibility study (PIT-STOP)
Funder: Department of Health and Social Care

Abstract: BACKGROUND: Radiotherapy is commonly used in the management of HNC patients. Approximately more than half of irradiated HNC patients will experience RIF as permanent adverse effect (approximately 4,200 per year in UK). RIF presents as hardness and stiffness of the facial/masticatory muscles leading to restriction in mouth opening [trismus] and consequent reduced ability to talk, chew food, and maintain a good oral hygiene. RIF can also cause hardening of the oropharyngeal muscles, with consequent impairment of swallowing [dysphagia], which can lead to aspiration and increased risk of pneumonia and fatality. Overall, HNC survivors who develop RIF have significant morbidity, reduced quality of life, and no realistic therapeutic option as no intervention has proven effective. Major psychological and social issues, as well as malnutrition, are common. Mortality is also increased due to aspiration pneumonia associated with dysphagia. AIMS: The aim of PIT-STOP is to carry out feasibility work so to consider the feasibility, acceptability as well as to inform important aspects of the design of a substantive clinical trial (main study) that will investigate effectiveness of the treatment with pentoxifylline and tocopherol in reversing RIF in HNC survivors. DESIGN: Feasibility study of 6 months of Pentoxifylline and Tocopherol treatment in addition to Current Best Practice (rehabilitation speech therapy) vs Current Best Practice in HNC survivors with established RIF [trismus and/or dysphagia]: 50 participants will be recruited at two study sites and randomised 1:1 into the 2 arms of the study. Patient-centred outcome measures (validated questionnaires) and clinician-rated outcomes (validated trisums/dysphagia scales), as well as other subjective (Quality of Life questionnaires) and instrumental measurements (e.g. videofluoroscopy) will be used as measurements at baseline, at 1 and 3 months during treatment and at 6 months [endpoint]. The feasibility parameters that we plan to estimate include: ability to recruit patients, retention/drop out rate, compliance with the protocol, and feasibility of outcome measures. We also intend to estimate standard deviation of the anticipated primary outcome so to inform sample size calculation of the main trial, as well as explore feasibility of a range of additional potential outcome measures. The study will last 36 months including set up, recruitment, treatment and data analysis. BENEFIT TO PATIENTS: Given the lack of available therapies in this field, PIT-STOP has an exciting high potential to pave the way, within a timeframe (36 months) that is relatively short for curative interventions, for a subsequent methodologically sound trial that will focus on effectiveness (improvement of function and quality of life). The long-term main objective is to provide robust evidence regarding the effectiveness of pentoxifylline and tocopherol in reversing RIF so to speed up the translation of the intervention into NHS clinical practice for the benefit of patients within a timeframe of less than 10 years (as opposite to an average of 17 years historically required to implement a proven healthcare innovation into standard medical care). Also, appropriate management of long-term consequences of cancer treatment is known to translate into a faster return to work, and consequent reduction in lost income and costs of trips to the hospital, with clear benefits to the individual and also the wider economy due to reduced lost productivity. BENEFIT TO NHS: We expect no immediate benefit from the fasibility phase. However the future main study has the potential to bring to the NHS a treatment for a condition that has currently no realistic therapy. Financial benefits are also expected: a non-invasive effective treatment for RIF in HNC survivors would prevent the risk of complications [e.g. aspiration pneumonia], with an overall reduction in long-term NHS treatment costs.

Lay abstract: BACKGROUND: Cancer of the head and neck, which includes malignancy of the mouth and throat, is an increasingly common disease in UK (10,000 cases/year). Radiotherapy is a standard treatment in most patients; however it is often complicated by a permanent adverse effect known as fibrosis. Fibrosis is characterised by hardening of mouth muscles, as well as those of the pharynx and throat. Affected individuals have restricted mouth opening and reduced ability to talk and chew food (known as trismus), as well as difficulty in swallowing food and liquids (known as dysphagia). This has a significant impact on the quality of life, can cause malnutrition and also life-threatening pneumonia due to entrance of food/liquids into the respiratory tract. There remains no effective treatment and research in this field is limited. A POTENTIAL SOLUTION: ANTI-FIBROTIC DRUG THERAPY: pentoxifylline and tocopherol are medications that have been used to reverse fibrosis of radiotherapy in individuals who had cancer of the breast, pelvis, lung, and prostate. It is not known whether these medications may have similar beneficial effects also in head and neck cancer survivors. Preliminary small-scale studies suggest that these medications represent a promising anti-fibrotic treatment that is worth investigating in well-designed clinical trials. THE NEED FOR A FEASIBILITY STUDY: A large multicentre randomised trial would be needed to show the benefits of pentoxyfilline and tocopherol anti-fibrotic therapy in head and neck cancer survivors. We propose that feasibility work is needed to demonstrate that such a study would be feasible and acceptable to patients. PIT-STOP will estimate important aspects of the main study including ability to recruit and acceptability of the intervention. Other parameters to be investigated include feasibility and acceptability of study measurements (outcomes) and collection of data to clarify how many subjects should be recruited in the main trial.

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