SAVER: sodium valproate for the epigenetic reprogramming of high-risk oral epithelial dysplasia-a phase II randomised control trial study protocol.

BACKGROUND: Sodium valproate (VPA) has been associated with a reduced risk of head and neck cancer development. The potential protective mechanism of action is believed to be via inhibition of histone deacetylase and subsequent epigenetic reprogramming. SAVER is a phase IIb open-label, randomised control trial of VPA as a chemopreventive agent in patients with high-risk oral epithelial dysplasia (OED). The aim of the trial is to gather preliminary evidence of the clinical and biological effects of VPA upon OED and assess the feasibility and acceptability of such a trial, with a view to inform a future definitive phase III study. METHODS: One hundred and ten patients with high-risk OED will be recruited from up to 10 secondary care sites in the UK and randomised into either VPA or observation only for 4 months. Women of childbearing potential will be excluded due to the teratogenic properties of VPA. Tissue and blood samples will be collected prior to randomisation and on the last day of the intervention/observation-only period (end of 4 months). Clinical measurement and additional safety bloods will be taken at multiple time points during the trial. The primary outcome will be a composite, surrogate endpoint of change in lesion size, change in grade of dysplasia and change in LOH profile at 8 key microsatellite regions. Feasibility outcomes will include recruitment targets, compliance with the study protocol and adverse effects. A qualitative sub-study will explore patient experience and perception of the trial. DISCUSSION: The current management options for patients with high-risk OED are limited and mostly include surgical resection and clinical surveillance. However, there remains little evidence whether surgery can effectively lead to a notable reduction in the risk of oral cancer development. Similarly, surveillance is associated with concerns regarding delayed diagnosis of OED progressing to malignancy. The SAVER trial provides an opportunity to investigate the effects of a repurposed, inexpensive and well-tolerated medication as a potential chemopreventive strategy for patients with high-risk OED. The clinical and biological findings of SAVER will inform the appropriateness, design and feasibility of a definitive phase III trial. TRIAL REGISTRATION: The trial is registered with the European Clinical Trials Database ( Eudra-CT 2018-000197-30 ). ( http://www.isrctn.com/ISRCTN12448611 ). The trial was prospectively registered on 24/04/2018.

HOPON (Hyperbaric Oxygen for the Prevention of Osteoradionecrosis): A Randomized Controlled Trial of Hyperbaric Oxygen to Prevent Osteoradionecrosis of the Irradiated Mandible After Dentoalveolar Surgery.

PURPOSE: Hyperbaric oxygen (HBO) has been advocated in the prevention and treatment of osteoradionecrosis (ORN) of the jaw after head and neck radiation therapy, but supporting evidence is weak. The aim of this randomized trial was to establish the benefit of HBO in the prevention of ORN after high-risk surgical procedures to the irradiated mandible. METHODS AND MATERIALS: HOPON was a randomized, controlled, phase 3 trial. Participants who required dental extractions or implant placement in the mandible with prior radiation therapy >50 Gy were recruited. Eligible patients were randomly assigned 1:1 to receive or not receive HBO. All patients received chlorhexidine mouthwash and antibiotics. For patients in the HBO arm, oxygen was administered in 30 daily dives at 100% oxygen to a pressure of 2.4 atmospheres absolute for 80 to 90 minutes. The primary outcome measure was the diagnosis of ORN 6 months after surgery, as determined by a blinded central review of clinical photographs and radiographs. The secondary endpoints included grade of ORN, ORN at other time points, acute symptoms, pain, and quality of life. RESULTS: A total of 144 patients were randomized, and data from 100 patients were analyzed for the primary endpoint. The incidence of ORN at 6 months was 6.4% and 5.7% for the HBO and control groups, respectively (odds ratio, 1.13; 95% confidence interval, 0.14-8.92; P = 1). Patients in the hyperbaric arm had fewer acute symptoms but no significant differences in late pain or quality of life. Dropout was higher in the HBO arm, but the baseline characteristics of the groups that completed the trial were comparable between the 2 arms. CONCLUSIONS: The low incidence of ORN makes recommending HBO for dental extractions or implant placement in the irradiated mandible unnecessary. These findings are in contrast with a recently published Cochrane review and previous trials reporting rates of ORN (non-HBO) of 14% to 30% and challenge a long-established standard of care.

HOPON (Hyperbaric Oxygen for the Prevention of Osteoradionecrosis): a randomised controlled trial of hyperbaric oxygen to prevent osteoradionecrosis of the irradiated mandible: study protocol for a randomised controlled trial.

BACKGROUND: Osteoradionecrosis of the mandible is the most common serious complication of radiotherapy for head and neck malignancy. For decades, hyperbaric oxygen has been employed in efforts to prevent those cases of osteoradionecrosis that are precipitated by dental extractions or implant placement. The evidence for using hyperbaric oxygen remains poor and current clinical practice varies greatly. We describe a protocol for a clinical trial to assess the benefit of hyperbaric oxygen in the prevention of osteoradionecrosis during surgery on the irradiated mandible. METHODS/DESIGN: The HOPON trial is a phase III, randomised controlled, multi-centre trial. It employs an unblinded trial design, but the assessment of the primary endpoint, i.e. the diagnosis of osteoradionecrosis, is assessed on anonymised clinical photographs and radiographs by a blinded expert panel. Eligibility is through the need for a high-risk dental procedure in the mandible where at least 50-Gy radiotherapy has been received. Patients are randomised 1:1 to hyperbaric oxygen arm (Marx protocol) : control arm, but both groups receive antibiotics and chlorhexidine mouthwash. The primary endpoint is the presence of osteoradionecrosis at 6 months following surgery, but secondary endpoints include other time points, acute symptoms and pain, quality of life, and where implants are placed, their successful retention. DISCUSSION: The protocol presented has evolved through feasibility stages and through analysis of interim data. The classification of osteoradionecrosis has undergone technical refinement to ensure that robust definitions are employed. The HOPON trial is the only multi-centre RCT conducted in this clinical setting despite decades of use of hyperbaric oxygen for the prevention of osteoradionecrosis. TRIAL REGISTRATION: European Clinical Trials Database, ID: EudraCT200700622527 . First registered on 5 November 2007.

Refining the definition of mandibular osteoradionecrosis in clinical trials: The cancer research UK HOPON trial (Hyperbaric Oxygen for the Prevention of Osteoradionecrosis).

INTRODUCTION: Mandibular osteoradionecrosis (ORN) is a common and serious complication of head and neck radiotherapy for which there is little reliable evidence for prevention or treatment. The diagnosis and classification of ORN have been inconsistently and imprecisely defined, even in clinical trials. METHODS: A systematic review of diagnosis and classifications of ORN with specific focus on clinical trials is presented. The most suitable classification was evaluated for consistency using blinded independent review of outcome data (clinical photographs and radiographs) in the HOPON trial. RESULTS: Of 16 ORN classifications found, only one (Notani) appeared suitable as an endpoint in clinical trials. Clinical records of 217 timepoints were analysed amongst 94 randomised patients in the HOPON trial. The only inconsistency in classification arose where minor bone spicules (MBS) were apparent, which occurred in 19% of patients. Some trial investigators judged MBS as clinically unimportant and not reflecting ORN, others classified as ORN based on rigid definitions in common clinical use. When MBS was added as a distinct category to the Notani classification this ambiguity was resolved and agreement between observers was achieved. DISCUSSION: Most definitions and clinical classifications are based on retrospective case series and may be unsuitable for prospective interventional trials of ORN prevention or treatment. When ORN is used as a primary or secondary outcome in prospective clinical trials, the use of Notani classification with the additional category of MBS is recommended as it avoids subjectivity and enhances reliability and consistency of reporting.