Hyperbaric Oxygen Treatment of Mandibular Osteoradionecrosis. A Randomized Clinical Study
Primary Purpose
Osteoradionecrosis
Status
Unknown status
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Hyperbaric oxygen
Sponsored by
About this trial
This is an interventional treatment trial for Osteoradionecrosis focused on measuring osteoradionecrosis, hyperbaric oxygen, sequestrectomy
Eligibility Criteria
Inclusion Criteria:
- Osteoradionecrosis grade 2, 3 or 4 according to the CTCAE v 3.0 criteria
- Localized to the mandibula
- > 18 yrs old
Exclusion Criteria:
- Existing malignant disease
- Previous HBO
- Pregnancy or lactation
- Uncontrollable claustrophobia
- Undrained pneumothorax
- Blood pressure > 220/110
- Exposed titanium reconstruction device
Sites / Locations
- Aarhus University HospitalRecruiting
- Department of Anaesthesia, Copenhagen University HospitalRecruiting
- Sahlgrenska UniversitetRecruiting
- Aintree University Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
No Intervention
Arm Label
1
2
Arm Description
30 preoperative HBO sessions, sequestrectomy and 10 postoperative HBO sessions. The duration of each session is 90 minutes. 100 % oxygen is inhaled during decompression to 2.4 ATA.
Sequestrectomy without HBO treatment
Outcomes
Primary Outcome Measures
Osteoradionecrosis status according to the National Cancer Institute Common Toxicity Criteria v 3.0
Secondary Outcome Measures
Life Quality
EORTC QoL-30 and H&N35
Body mass index
Body mass index
Pain intensity
Pain intensity on a VAS scale and based on analgetics consumption
Trismus
Ability to open the mouth
Xerostomia
Questionnaire
Dysphagia
Dysphagia according to the National Cancer Institute Common Toxicity Criteria v 3.0
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00760682
Brief Title
Hyperbaric Oxygen Treatment of Mandibular Osteoradionecrosis. A Randomized Clinical Study
Official Title
Hyperbaric Oxygen Treatment of Mandibular Osteoradionecrosis. A Randomized Clinical Study
Study Type
Interventional
2. Study Status
Record Verification Date
May 2012
Overall Recruitment Status
Unknown status
Study Start Date
June 2008 (undefined)
Primary Completion Date
April 2015 (Anticipated)
Study Completion Date
April 2015 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Lone Forner
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
There is currently not sufficient evidence that hyperbaric oxygen (HBO) benefits the surgical removal of necrotic bone in osteoradionecrosis patients. This study aims at testing the hypothesis that HBO does improve healing after surgical removal of necrotic bone in irradiated previous head and neck cancer patients compared to not receiving HBO.
Detailed Description
Study objective
The objective of the study is to evaluate the effect of hyperbaric oxygen (HBO) on mandibular osteoradionecrosis as an adjunctive to surgical treatment in patients previously irradiated for head and neck cancer.
Hypothesis: Osteoradionecrosis lesions heal more frequently when administering HBO as an adjunct to surgery.
Introduction and rationale
Each year, 300 danish patients are diagnosed with oral cancer. The majority of these cancers are planocellular carcinomas. The established treatments are surgery and radiation therapy. Depending on multiple factors such as total radiation dose, fractionation, localization and use of brachytherapy, mandibular osteradionecrosis occurs in 5-15% of previously head and neck irradiated patients.
Osteradionecrosis is defined by National Cancer Institute (NCI) as radiation-induced cell death in components of bone (e.g., the marrow fat and mineralized tissue). It represents the final common pathway of several disease entities, which result in impaired blood supply to the bone tissue causing bone necrosis. Often, osteoradionecrosis is clinically expressed in relation to surgery or a similar tissue trauma, but may also arise spontaneously several years after radiation treatment. Oral rehabilitation is difficult in these patients as denture wear is painful. Furthermore, radiation-induced hyposalivation complicates retention of dentures, which are normally retained by a thin saliva film. As denture wear appears difficult, insertion of implants seems obvious in these patients. However, the survival rate of dental implants are reduced when inserted in irradiated bone. Thus, osteoradionecrosis patients has great requirements regarding pain therapy as well as oral functional and social rehabilitation.
HBO is currently offered to osteoradionecrosis patients as a standard treatment in combination with surgical removal of the necrotic bone (sequestrectomy). 30 preoperative and 10 postoperative treatment sessions are given daily (on weekdays) during eight weeks. The duration of each treatment session is 90 minutes and involves inhalation of 100% oxygen during decompression to 15 meters (2.5 ATA). The decompression leads to an increased oxygen tension in the tissues. HBO stimulates monocyte and fibroblast proliferation as well as collagen synthesis in irradiated tissue. Also, angiogenesis is stimulated, resulting in an increased vascularity. Moreover, recent research shows that HBO induces bone marrow derived progenitor cells in previously irradiated humans and animals.
At this point, there is not sufficient scientific evidence for a clinical effect of HBO on osteoradionecrosis. The majority of relevant studies are casuistic reports and case-control studies with few participants. Few randomized clinical trials (RCT) have been conducted. Two of these studies document an effect of HBO, but one of the studies only include twelve participants, which is not associated with sufficient power. The other study document a prophylactic effect of HBO on osteoradionecrosis, and does therefore not conclude on any treatment effects. The authors of the third study conclude, that there is no effect of HBO treatment. However, in this study, the protocol was closed before full inclusion (68 vs. 222), and therefore, the power may not be sufficient. Furthermore, the study protocol lacks accordance with the standard HBO protocol and sufficient description of the surgical interventions. Moreover, there is an unrealistically high recovery rate in the control group with following risk of drawing the wrong conclusions.
A Cochrane review states that there is not sufficient amounts of data to perform a meta-analysis. Thus, more randomized clinical studies are needed in order to document whether there is an effect of HBO on osteoradionecrosis.
Endpoints
3.1. Primary endpoint The primary endpoint recovery from osteoradionecrosis as defined by the NCI Common Toxicity Criteria of Adverse Events (CTCAE) v 3.0. Recovery is defined as no signs of osteoradionecrosis according to these criteria or grade 1 on this scale.
Grade 1: Asymptomatic, radiographic findings only. Grade 2: Symptomatic and interfering with function, but not interfering with ADL (Activities of Daily Living , , , ). Minimal bone removal indicated i.e. minor sequestrectomy)..
Grade 3: Symptomatic, interfering with ADL. Operative intervention or hyperbaric oxygen indicated.
Grade 4: Disabling Grade 5: Death
3.2. Secondary endpoints
Life quality (EORTC schemes QLQ-C30, QLQ-H&N35)
Body Mass Index
Pain intensity (VAS)
Analgetics consumption
Antibiotics consumption
Trismus
Xerostomia
Dysphagia
Dental status
CTCAE v. 3.0 is based on clinical as well as ADL related criteria. The primary endpoint value is obtained by filling out 21-05 and 21-06. The ORN stadium is the highest obtained score. In patients not wearing dentures, the denture-related question can be omitted.
Investigational plan
4.1. Inclusion
All patients eligible for the study will be asked for informed consent by the protocol responsible person. If the patient does not wish to participate in the study, standard treatment will be given (HBO and surgery). Verbal and written information about the study will be given during the preliminary investigation. Randomization will occur approximately one week prior to participation.
4.1. Study plan
After confirmation of study eligibility, the participant is randomized to either group I (HBO and surgery) or group II (surgery).
Drug registration is performed at home until 3 months postsurgically. After this point, information is obtained from a central register.
The study is not blinded, as we consider it unrealistic to blind the investigator because of risk of 1) the participant unintentionally mentions details from the HBO treatment or that the investigator runs into the patient at the hyperbaric facility.
The trials is ended when 114 participants are included. Participants withdrawn from the study will be replaced until 114 have completed participation. A drop-out rate of 20-30% is considered likely, which means that in total, 150 potential participants will be asked to participate in order to obtain 114 observations. The drop-out The drop-out rate will be evaluated throughout the study. All patients eligible for the study will be asked for informed consent by the protocol responsible person. If the patient does not wish to participate in the study, standard treatment will be given (HBO and surgery). Verbal and written information about the study will be given during the preliminary investigation. Randomization will occur approximately one week prior to participation.
Prior to participation
Prior to inclusion, the participants is examined by a hyperbaric physician and a head and neck surgeon to ensure that the following criteria are met.
Inclusion criteria
Osteoradionecrosis grade 2, 3 or 4 (CTCAE v 3.0.)
Localization: Mandibula
Age > 18 No contraindications for hyperbaric oxygen treatment, e.g. emphysema, uncontrolled asthma, epilepsy, previous optic neuritis
Exclusion criteria solely applies for HBO treatment. Should any criteria arise after the HBO treatment, it is unnecessary to withdraw the patient from participation.
Malignancy/residual cancer
Previous HBO treatment
Pregnancy or lactation (fertile female participants are required to use safe anticonception)
Unmanageable claustrophobia
Undrained pneumothorax
Uncontrollable hypertension or blood pressure >220/110
Explosion of titanium reconstruction device
5.2. Clinical evaluation prior to treatment
Examination at baseline is carried out using the existing HBO examination programme and includes following anamnestic registrations:
§ Epilepsy
§ Lung disease
§ Heart disease
§ Diabetes
Psychologic or psychiatric disorders (to evaluate the need for medication during HBO)
Drug list
Use of eyeglasses
Objective examination
§ Ability to equalize the pressure in the ears and sinuses (otherwise drained)
§ Heart and lung stetoscopy
Blood pressure
Weight
Pain assessment (VAS)
5.3. Inclusion, randomization and stratification. For all eligible patients with informed consent, a DAHANCA 21-inclusion form, which is a checklist for inclusion- and exclusion criteria is filled out and faxed to the DAHANCA office: Fax +45 86 19 71 09. The fax is returned with randomization number and treatment regimen.
Included patients will be stratified according to
Gender
ORN stadium
6. Treatment
All patients will be followed closely during their treatment. The investigator will perform the evaluations blinded. Since HBO treatment is time-consuming (8 weeks) and expensive (2000 DKK per session), it is not possible, nor ethically acceptable, to include a placebo group in order to conduct the study blinded to the participants.
6.1. Hyperbaric oxygen treatment
The patient will be decompressed according to a standard profile used in the clinic. During the first five minutes, the patient is decompressed to 14,5 +/- 0,5 m (2,45 +/- 0,05 ATA) and stays here for the next 90 minutes. Decompression to the surface (0 m) will hereafter take place during five minutes. The patient will breathe 100% oxygen during the full 100-minute procedure inside a hood (Amron Systems, California, USA) or mask (Divex Hyperlite II (Divex Industries, Aberdeen, Scotland). Each patient receives 30 preoperative treatment and 10 postoperative treatments.
6.2. Surgical treatment
All patients with ORN grade >1 will be surgically treated according to standardized guidelines. The interventions implies either
Resection of necrotic bone (sequestrectomy) with preservation of mandibular continuity.
Resection of necrotic bone (sequestrectomy) with loss of mandibular continuity. The least mutilating intervention will be performed. Resection with loss of continuity will only be performed in case of potential or stated fracture.
6.3. Termination of participation
Protocol treatment will be terminated in case:
The patient wish to terminate participation. New indication for surgery arises because of osteoradionecrosis at another localization.
Other unintentional events occurs that may impede participation.
7. Clinical evaluation and follow-up
7.1. One week after sequestrectomy The first evaluation occurs one week after surgery in order to evaluate wound healing.
7.2. One month after sequestrectomy (+/- two weeks).
7.3. Three months after sequestrectomy (+/- three weeks).
7.4. One year after sequestrectomy (+/- one month).
7.5. After relapse/progression In case of relapse or progression patients are treated according to local guidelines.
7.6 Follow-up
All patients are followed once a year for at least 5 years after completion of participation. Additionally, patients are instructed to contact the department in case of relapse.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Osteoradionecrosis
Keywords
osteoradionecrosis, hyperbaric oxygen, sequestrectomy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
114 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
1
Arm Type
Experimental
Arm Description
30 preoperative HBO sessions, sequestrectomy and 10 postoperative HBO sessions. The duration of each session is 90 minutes. 100 % oxygen is inhaled during decompression to 2.4 ATA.
Arm Title
2
Arm Type
No Intervention
Arm Description
Sequestrectomy without HBO treatment
Intervention Type
Procedure
Intervention Name(s)
Hyperbaric oxygen
Intervention Description
30 preoperative and 10 postoperative HBO sessions 90 minutes each. Sequestrectomy is performed after 30 sessions.
Primary Outcome Measure Information:
Title
Osteoradionecrosis status according to the National Cancer Institute Common Toxicity Criteria v 3.0
Time Frame
1 year
Secondary Outcome Measure Information:
Title
Life Quality
Description
EORTC QoL-30 and H&N35
Time Frame
1 year
Title
Body mass index
Description
Body mass index
Time Frame
1 year
Title
Pain intensity
Description
Pain intensity on a VAS scale and based on analgetics consumption
Time Frame
1 year
Title
Trismus
Description
Ability to open the mouth
Time Frame
1 year
Title
Xerostomia
Description
Questionnaire
Time Frame
1 year
Title
Dysphagia
Description
Dysphagia according to the National Cancer Institute Common Toxicity Criteria v 3.0
Time Frame
1 year
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Osteoradionecrosis grade 2, 3 or 4 according to the CTCAE v 3.0 criteria
Localized to the mandibula
> 18 yrs old
Exclusion Criteria:
Existing malignant disease
Previous HBO
Pregnancy or lactation
Uncontrollable claustrophobia
Undrained pneumothorax
Blood pressure > 220/110
Exposed titanium reconstruction device
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Lone Forner, DDS; PhD
Phone
+45 35 45 82 11
Email
lone.forner@rh.regionh.dk
First Name & Middle Initial & Last Name or Official Title & Degree
Erik Jansen, MD, DMSc
Phone
+45 35 45 12 57
Email
erik.jansen@rh.regionh.dk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lone Forner, DDS, PhD
Organizational Affiliation
Copenhagen University Hospital at Herlev
Official's Role
Principal Investigator
Facility Information:
Facility Name
Aarhus University Hospital
City
Aarhus
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Per Johan Sixten Blomlöf
First Name & Middle Initial & Last Name & Degree
Malene Helleberg
Facility Name
Department of Anaesthesia, Copenhagen University Hospital
City
Copenhagen
ZIP/Postal Code
2100
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lone Forner, DDS, PhD
Phone
+45 35 45 82 11
Email
lone.forner@rh.regionh.dk
First Name & Middle Initial & Last Name & Degree
Erik Jansen, MD, DMSc
Phone
+45 35 45 12 57
Email
erik.jansen@rh.regionh.dk
First Name & Middle Initial & Last Name & Degree
Lone Forner, DDS, PhD
Facility Name
Sahlgrenska Universitet
City
Gothenburg
Country
Sweden
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Per Arnell
Facility Name
Aintree University Hospital
City
Liverpool
Country
United Kingdom
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Richard John Shaw
12. IPD Sharing Statement
Links:
URL
http://www.hbo.dk
Description
Related Info
Learn more about this trial
Hyperbaric Oxygen Treatment of Mandibular Osteoradionecrosis. A Randomized Clinical Study
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