Trial Information

Hyperbaric Oxygen Treatment of Mandibular Osteoradionecrosis. A Randomized Clinical Study

1. 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.

2. 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.

3. 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.

4. 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.

5. 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

1. Osteoradionecrosis grade 2, 3 or 4 (CTCAE v 3.0.)

2. Localization: Mandibula

3. 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.

1. Malignancy/residual cancer

2. Previous HBO treatment

3. Pregnancy or lactation (fertile female participants are required to use safe
anticonception)

4. Unmanageable claustrophobia

5. Undrained pneumothorax

6. Uncontrollable hypertension or blood pressure >220/110

7. 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

1. Resection of necrotic bone (sequestrectomy) with preservation of mandibular continuity.

2. 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.