Neoplasms

All Conditions

Wounds and Injuries

Head and Neck Neoplasms

Osteoradionecrosis

Radiation Injuries

Anti-Infective Agents

All Drugs and Chemicals

Antineoplastic Agents

Vasodilator Agents

Platelet Aggregation Inhibitors

Micronutrients

Bone Density Conservation Agents

Vitamins

Amoxicillin

Ciprofloxacin

Clavulanic Acid

Pentoxifylline

Tocopherols

Vitamin E

Tocotrienols

alpha-Tocopherol

Fluconazole

Anti-Infective Agents, Local

Clavulanic Acids

Clodronic Acid

Phosphodiesterase Inhibitors

Enzyme Inhibitors

Protective Agents

Radiation-Protective Agents

Antioxidants

Trace Elements

Tocopherol

Tocotrienol

Standard of care treatment for ORN consisting of conservative measures (e.g. local irrigation, antiseptic mouthwash) and approximately 60 hyperbaric oxygen therapy (HBOT) treatments (90 minute exposures at 2.4 ATA each, scheduled Monday to Friday for 12 weeks - i.e., 5 treatments per week). At the conclusion of the study and at the discretion of the clinical team, patients randomized to the control group with residual disease may be considered for the mPENTOCLO protocol.

Simultaneously, the 4-week mPENTOCLO "pre-treatment" phase will be started (as defined in the intervention section), followed by a sham/placebo mPENTOCLO treatment phase for a total of 12 months.

Standard of care treatment as described for the control group (conservative measures and 60 HBOT treatments).

Simultaneously, a comprehensive oral regimen (mPENTOCLO) will be started, including a 4-week "pre-treatment phase" followed by a "treatment phase" for a total of 12 months, as defined in the Intervention section.

4-week "pre-treatment" phase consisting of 2 g daily of Amoxicillin+Clavulanic acid 875/125 mg (1 g morning and night), 1 g ciprofloxacin (500 mg morning and night) and 50 mg Fluconazole daily (morning), taken orally by the patient.

This is followed by an additional 11 months (12 months total) "treatment" phase consisting of 800 mg pentoxifylline (400 mg morning and night) and 800 IU tocopherol (400 IU morning and night) taken orally 5 days per week (Monday to Friday with no medications on Saturday and Sunday). If the patient deteriorates (i.e., worsening of ORN T 6 or 9-month follow-up) then clodronate 1600 mg once daily (Monday to Friday) for the rest of the study period will be added.

modified PENTOCLO (mPENTOCLO)

4-week "pre-treatment" phase consisting of 2 g daily of Amoxicillin+Clavulanic acid 875/125 mg (1 g morning and night), 1 g ciprofloxacin (500 mg morning and night) and 50 mg Fluconazole daily (morning), taken orally by the patient.

This is followed by an additional 11 months (12 months total) of sham "treatment" phase (placebo).

sham mPENTOCLO

Ben Safa, MD

Radiation is commonly used to treat cancer in the head and neck, however, this can lead to a serious complication called osteoradionecrosis (ORN), where there is necrotic (dead) open bone inside or outside of the mouth. This complication is difficult to treat, involves large healthcare costs, and can have devastating effects on quality of life.

Two common adjuncts used in treatment of ORN are hyperbaric oxygen therapy (HBOT), which may requires up to 60 treatments at a specialized clinic where patients are treated with high concentrations of oxygen using special chambers, and a less complex option called PENTOCLO which involves treating patients with several antibiotics followed by a combination of other oral medications taken for at least 1 year.

This pilot study will be guide the design of a definitive trial to examine if the combination of HBOT and a modified PENTOCLO protocol together is better than the current standard treatment of HBOT alone. Outcomes will include pain, side effects and the need for surgery in patients with ORN. Specifically, the results of this small, pilot study will help to inform the design of a future larger study.

Osteoradionecrosis (ORN) of the mandible is a potentially devastating complication which can occur following radiation therapy for head and neck cancers. ORN is difficult to treat using standard methods, and is associated with high healthcare costs and potentially dire impacts on quality of life. In addition to conservative measures (e.g. antibiotics, local irrigation, oral care) and surgical management, there are two established adjuvant treatments for ORN: hyperbaric oxygen therapy (HBOT) and an oral regimen called PENTOCLO, which consists of pre-treatment with oral antibiotics followed by prolonged treatment with a combination of PENtoxifylline, TOcopherol (Vitamin E) and CLOdronate.

This will be the first study to investigate the potential benefits of combining HBOT and a modified PENTOCLO regimen for treatment of ORN. This study is a prospective, pilot, open label, outcome blinded, randomized controlled trial where participants with a confirmed diagnosis of mandibular ORN will be randomized (1:1 in blocks of 4, stratified by ORN stage) to receive either the standard HBOT treatment or HBOT plus a modified PENTOCLO regimen.

The primary objective of this pilot trial is to determine feasibility of a larger definitive trial by assessing recruitment, adherence to the interventional protocol, ability to achieve 12 months follow up, feasibility of completing outcome measures, and study costs (including research support and healthcare resources costs per patient). Clinical outcomes including improvement or worsening of ORN of the mandible after 12-month treatment will also be assessed.

Participants will be followed for 12 months from the start of treatment, with follow-ups at 4 weeks, 5/6 weeks, and 3, 6, 9, and 12 months to assess pain scores, ORN characteristics, quality of life and adverse events.

Prospective, pilot, double blind, randomized (stratified to ORN stage), controlled trial

One unblinded clinician will be required for management of side effects and dose adjustments of pentoxifylline and clodronate as required in the event of side effects or intolerance. However, all other participants including, patients, assessors, research team and data analysts will be blinded to group allocation. At standard follow-up examination, imaging and photographs will be taken and de-identified and then presented to a blinded oral and maxillofacial surgeon for EBA calculation and to a blinded radiologist for allocation of Notani classification grade.

Combination Therapy: Hyperbaric Oxygen and PENTOCLO for Treatment of Osteoradionecrosis of the Mandible

Combination Therapy: Hyperbaric Oxygen and PENTOCLO for Treatment of Osteoradionecrosis of the Mandible, a Pilot Randomized Control Trial

De-identified participant-level data will be made available upon reasonable request to study PI following publication of full trial results.

Assessed using Xerostomia Inventory and/or Clinical Oral Dryness Score

Medications and dosages (oral morphine equivalents) currently being taken by participants at each scheduled follow-up

Assessed using Numerical Rating Scale (NRS) patient to rate their pain on scale of 0-10 where 0 is no pain and 10 is the worst pain imaginable

Recruitment of two subjects per month on average over 12 months

At least 70% of all eligible patients are recruited

More than 80% of all recruited subjects complete 60 sessions of HBOT (20/24)

More than 80% of patients in mPENTOCLO group complete mPENTOCLO protocol (10/12)

Investigators to keep logs of time required to perform study related work

Cost of study including research support and healthcare resource costs per patient

Proportion of patients reaching recovery within the study period in each group. "Recovery" will be defined as the absence of pain, pathologic fracture, and cutaneous fistula; exposed bone area (EBA) less than 20 mm2; and by evidence of stabilization or regression on radiographic findings (Notani classification score). Minor bone spicules of less than 20 mm2 that have no ongoing pain, and no radiographic abnormalities will be considered fully healed and not Notani grade 1.

Difference in time required to reach recovery in each group. "Recovery" will be defined as the absence of pain, pathologic fracture, and cutaneous fistula; exposed bone area (EBA) less than 20 mm2; and by evidence of stabilization or regression on radiographic findings (Notani classification score). Minor bone spicules of less than 20 mm2 that have no ongoing pain, and no radiographic abnormalities will be considered fully healed and not Notani grade 1.

Notani Classification Score

I ORN confined to dentoalveolar bone II ORN limited to dentoalveolar bone or mandible above the inferior dental canal, or both III ORN involving the mandible below the inferior dental canal, or pathological fracture, or skin fistula

Late Effects Normal Tissue Task Force-Subjective, Objective, Management and Analytic (LENT-SOMA) score

Complications related to HBOT and/or mPENTOCLO, as defined in product monographs and study protocol.

Spots Global Cancer Trial Database for modified pentoclo (mpentoclo)