Leading Clinical Paper

Head, Neck Oncology

The inuence of hyperbaric
oxygen on the outcome of
patients treated for
osteoradionecrosis: 8 year
study
J. DSouza, J. Goru, S. Goru, J. Brown, E. D. Vaughan, S. N. Rogers: The inuence
of hyperbaric oxygen on the outcome of patients treated for osteoradionecrosis: 8 year
study. Int. J. Oral Maxillofac. Surg. 2007; 36: 783787. # 2007 International
Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights
reserved.
J. DSouza
1
, J. Goru
2
, S. Goru
2
,
J. Brown
1
, E. D. Vaughan
1
,
S. N. Rogers
1
1
Regional Maxillofacial Unit, University
Hospital Aintree, Liverpool, L97AL, UK;
2
Royal Liverpool University Dental Hospital,
Liverpool, UK
Abstract. This study was a retrospective review of treatment outcomes of
osteoradionecrosis (ORN) of the mandible over an 8-year period, with specic
reference to the role of hyperbaric oxygen therapy (HBOT). The presentation and
management of 23 patients treated for ORN was studied by categorising them into
three grades according to the severity of clinical and radiographic involvement. At
presentation there were 13 patients with grade I ORN, six patients with grade II
ORN and four patients with grade III ORN. HBOT was given to 10 patients in the
grade I group, four patients in the grade II group and two patients in the grade III
group. Overall eight patients (62%) with grade I, three patients (50%) with grade II
and two patients (50%) with grade III were cured. In the patients who received
HBOT the cure rate was 12.5%whilst in those without HBOT it was 86%. Although
the cohort was small it seems that HBOT was of little benet. HBOT is demanding
for patients and has cost implications for the NHS; hence further clinical outcome
data are urgently required with regard to its role in the management of ORN.
Key words: hyperbaric oxygen therapy; osteor-
adionecrosis; radiotherapy; surgery.
Accepted for publication 16 May 2007
Available online 5 July 2007
Osteoradionecrosis (ORN) is a severe com-
plication of bone irradiation. Although it
can occur at any time after radiation ther-
apy, 7094% of these events have been
reported to develop within the rst 3
years
9,11
. The incidence of ORN of the
mandible varies from2.6 to 22%; the range
is most commonly from 5 to 15% in recent
reports
6,22,24
.
There is controversy over the most sui-
table treatment for ORN. In addition to
surgery, hyperbaric oxygen therapy
(HBOT) has been used in prevention
and treatment of this condition. The ratio-
nale for using HBOT is to revascularize
the tissue and increase broblast numbers.
The ability of HBOT to induce angiogen-
esis in radiation-damaged tissue has been
documented
15,16
Prior to the availability
of HBOT and microvascular free tissue
transfer, the outcome of reconstruction
Int. J. Oral Maxillofac. Surg. 2007; 36: 783787
doi:10.1016/j.ijom.2007.05.007, available online at http://www.sciencedirect.com
0901-5027/090783 +05 $30.00/0 #2007 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
following ORN was poor; HBOT seemed
to improve the success rate in selected
cases
10,14
. MARX & JOHNSON
16
and MARX
et al.
17
have reported the benecial effect
of HBOT in the treatment of ORN using a
standardized protocol, which included
antibiotics, surgery and HBOT.
Despite the support for use of HBOT in
the prevention and treatment of ORN,
there seems to be little standardization
in its delivery and uncertainty about its
role
12
. MAIER et al.
13
have reported good
success rates in the management of ORN
without the use of HBOT and in conclu-
sion do not recommend HBOT. Similarly,
WONG et al.
24
have shown the effective-
ness of conservative treatment without
HBOT in resolving and stabilizing
ORN. ANNANE et al.
2
in a recent landmark
study showed that HBOT is not superior to
placebo and indeed raised concerns about
its damaging effects. The purpose of this
study was to review 8 years experience of
ORN affecting the mandible and compare
the outcomes of those patients who did
and who did not receive HBOT.
Method
Patients were identied from the Regional
Maxillofacial Oncology database and
were cross-referenced with records at
the Hyperbaric Oxygen Unit at Murray-
eld Hospital and Liverpool University
Dental Hospital Pathology Department.
All medical notes and radiographs were
available for review, and data were
extracted on presentation, radiotherapy
dose, HBOT, antibiotics, surgical treat-
ment, response and survival. Patients were
then divided into three grades based on the
classication system proposed by NOTANI
et al.
18
: grade I, ORN conned to alveolar
bone; grade II, ORNlimited to the alveolar
bone and/or mandible above the level of
inferior alveolar canal; grade III, ORN
involving the mandible below the level
of inferior alveolar canal and ORN with
a skin stula and/or pathologic fracture.
Results
Twenty-three patients treated for ORN
from 1996 to 2003 were included in the
study. There were 14 men and nine
women, with age at the time of diagnosis
of ORNranging from55 to 83 (mean 65.4)
years. Fifteen patients were dentate and
eight edentulous. The primary tumour
requiring radiotherapy was squamous cell
carcinoma in 22 patients and adenoid cys-
tic carcinoma in one patient. The location
of the primary tumour was oral cavity
(16), oropharynx (4), larynx (2) and par-
otid (1). The total dose of radiation ranged
from 50 to 86 (mean 64) Gy. The two
patients with laryngeal primaries had each
received 64 Gy of radiation. The time
from radiotherapy to diagnosis of ORN
varied from4 to 192 (mean 48) months. At
the time of diagnosis, 13 patients had
grade I ORN, six patients had grade II
ORN and four patients had grade III ORN.
Sixteen patients had received HBOT (10
grade I patients, four grade II patients, two
grade III patients). All patients had a
minimum follow up of at least 2.5 years.
Grade I patients (Table 1)
Thirteen patients had grade I ORN at the
time of diagnosis. Their age ranged from
56 to 83 (mean 66) years. Eight patients
were dentate and ve patients edentulous.
The dose of radiation ranged from50 to 86
(mean 61.6) Gy. The time from radiother-
apy to diagnosis of ORN varied from 5 to
168 (mean 36.6) months. All these patients
were managed conservatively in the rst
instance involving antibiotics and minimal
surgical debridement (curettage, removal
of necrotic bone and/or infected plate).
HBOT was given to 10 patients and the
number of dives ranged from 26 to 40.
Overall, ve patients responded favour-
ably to conservative treatment (cure rate 5/
13, 38%). HBOT seemed to confer little
benet as eight patients of the 10 who
received HBOT either progressed to stage
II and III or died with ORN still present.
Among those progressing to a higher
grade of ORN, one patient died whilst in
grade II due to lung cancer and the remain-
ing ve patients progressed to grade III
ORN. All these patients required multiple
surgical procedures such as plate removal
and application of external xator, but had
progressive disease, hence requiring
reconstruction with vascularized bone.
Overall in grade I, at the time of this
study, eight patients were alive (seven
ORN free, one ORN ongoing) and ve
dead (one ORN free, four ongoing ORN).
Among the deceased, the time from diag-
nosis of ORN to death varied from 2 to 20
(mean 9.8) months. The time from free
ap reconstruction to death ranged from
12 to 20 (mean 16) months.
Grade II patients (Table 2)
Six patients had grade II ORN at the time
of diagnosis. Their age at the time of
presentation ranged from 57 to 70 (mean
63.6) years. Five patients were dentate and
one patient edentulous. The dose of radia-
tion ranged from 60 to 70 (mean 66) Gy.
The time fromradiotherapy to diagnosis of
ORN varied from 4 to 84 (mean 37.5)
months. This group of patients received
multiple treatments with antibiotics and
surgical debridement. Four patients were
given HBOT and the number of dives
ranged from 28 to 40. Only one patient
was cured of ORN (cure rate 1/6, 17%).
This patient did not receive HBOT.
Another patient remained in grade II with
non-progressive disease. Four patients
progressed to grade III ORN and required
reconstruction with vascularized bone.
Two patients were cured.
784 DSouza et al.
Table 1. Grade I osteoradionecrosis
Patient Age
(years)
Radiation
dose (Gy)
Radiation to
ORN (months)
HBOT Outcome
of ORN
Additional
operation
Final
outcome
Survival
No. 1 83 56 132 Yes Cured None Cured Alive
No. 2 57 50 168 No Cured None Cured Alive
No. 3 67 54 5 No Cured None Cured Alive
No. 4 61 86 12 No Cured None Cured Alive
No. 5 68 64 6 Yes Present None Present Deceased
No. 6 66 60 5 Yes Present None Present Deceased
No. 7 59 60 16 Yes Cured None Present Alive
No. 8 64 64 24 Yes Grade II ORN Plate removal Present Deceased
No. 9 79 66 12 Yes Grade III ORN External xator Cured Deceased
No. 10 61 56 52 Yes Grade III ORN Free ap Cured Alive
No. 11 56 60 12 Yes Grade III ORN Free ap Present Alive
No. 12 64 60 24 Yes Grade III ORN Free ap Cured Alive
No. 13 74 66 8 Yes Grade III ORN Free ap Present Deceased
Overall in grade II, at the time of this
study, ve patients were alive (three ORN
free, two ORN ongoing) and one dead
(ongoing ORN). The only deceased patient
inthis groupdiedas a result of haemorrhage
from carotid artery 14 months following
diagnosis of ONR and had undergone free
ap reconstruction 3 months prior death.
Grade III patients (Table 3)
Four patients presented with grade III
ORN. Their age at the time of presentation
ranged from 64 to 83 (mean 69.2) years.
Two patients were dentate and 2 edentu-
lous. The dose of radiation ranged from 60
to 72 (mean 65.5) Gy. The time from
radiotherapy to diagnosis of ORN varied
from 6 to 192 (mean 93.2) months. All
these patients were deemed to require
radical surgery (segmental mandibulect-
omy and free ap reconstruction) and
underwent limited debridement to prepare
the recipient site for free tissue graft. Two
patients received 30 dives of HBOT. One
patient died of tumour recurrence ahead of
planned radical surgery. All remaining
three patients had segmental mandibular
resection and reconstruction with vascu-
larized bone. Two patients were cured of
ORN (cure rate 2/3, 67%). Neither of the
two cured patients had received HBOT.
Overall in grade III, at the time of this
study, no patients were alive (two patients
ORN free, two ORN ongoing). The time
from diagnosis of ORN to death varied
from4 to 72 (mean 28.2) months. The time
from free ap reconstruction to death ran-
ged from 2 to 64 (mean 26.2) months.
Discussion
In this retrospective study, a systematic
approach has been used to identify cases
of ORN over a period of 8 years (1996
2003) treated in a regional unit. Although
strenuous efforts have been made to iden-
tify all patients with ORN, it is acknowl-
edged that there may be a very small
number with very early ORN who might
have been treated at peripheral clinics and
never entered on to the database. The
cohort presented in this study reects all
the patients undergoing active treatment.
Various classication systems have
been proposed for ORN and they differ
in clinical value; for example, the classi-
cation proposed by MARX
15
and MARX &
JOHNSON
16
is only applicable for patients
who have received HBOT. Classications
such as the Late Effects of Normal Tis-
sue/Somatic Objective Management Ana-
lytic (LENT/SOMA)
9
are more suited to
prospective evaluations. Other systems,
such as those proposed by EPSTEIN
et al.
6
, NOTANI et al.
18
, STORE & BOYSEN
20
and SCHWARTZ & KAGAN
19
, are based on
clinical and radiographic involvement of
the jaw and seem to have more clinical
applicability. The classication system
proposed by NOTANI et al.
18
was used here
because it is easy to apply and separates
patients into 3 distinct grades based on
radiological appearances.
It is accepted that this cohort comprises
a small number of patients, but it reects
the activity over 8 years of a well recog-
nised regional unit in the UK. There is no
rigid protocol for the use of HBOT, but
since the HBOT unit is only about
15 miles from the Regional Maxillofacial
Unit, there has been a tendency in recent
years to suggest this treatment option to
patients and their carers.
Although numbers are small, HBOT
does not appear have a signicant inu-
ence. Among the grade I patients who had
received HBOT (77%, 10/13), only 20%
were cured; the remaining had ongoing
ORN. In contrast, all 3 patients who did
not receive HBOT were cured. In the
grade II group, none of the patients
who had received HBOT were cured,
whereas all three patients who did not
receive HBOT were cured with conser-
vative management. Similarly in the
grade III group, both the patients who
had received HBOT had ongoing ORN,
but the two patients who did not receive
HBOT were cured. Patients with poor
outcome who had HBOT did not neces-
sarily receive higher doses of radiation. It
is appreciated that not all patients
received HBOT in accordance with Marx
protocol. In some cases patients had to be
withdrawn from HBOT due to uncon-
trolled ORN that required urgent surgical
intervention for control of symptoms.
AITASALO et al.
1
have reported success
rates using a combination of HBOT and
decortication with periosteal grafting as a
successful treatment for ORN. Their pro-
tocol differs from Marx protocol
15,16
by
reducing the number of HBOT sessions
and hence cost.
The role and outcome of conservative
management for ORN is well established,
but need for radical surgery after conser-
vative treatment failure is reported to be as
high as 7083%
15,16,18
. In the present
study, conservative management failed
in 62% of grade I patients and 83% of
grade II patients. Although patients with
grade III ORN in this study were given
conservative treatment, the aim was not to
achieve a cure but to prepare a suitable
surgical bed for reconstruction.
HBOT has its strong advocates.
Numerous uncontrolled trials have been
reported with recovery rates of 1545%
with HBOT alone, and of 2090% with
HBOTcombined with surgery
3,10,25
. In an
The inuence of hyperbaric oxygen on the outcome of patients treated for osteoradionecrosis 785
Table 2. Grade II osteoradionecrosis
Patient Age
(years)
Radiation
dose (Gy)
Radiation to
ORN (months)
HBOT Outcome
of ORN
Additional
operation
Final
outcome
Survival
No. 1 70 70 4 Yes Cured None Cured Alive
No. 2 59 64 84 Yes Stable ORN None Stable Alive
No. 3 66 60 24 No Grade III ORN Free ap Cured Alive
No. 4 57 66 24 Yes Grade III ORN Free ap Present Deceased
No. 5 61 66 72 Yes Grade III ORN Free ap Present Alive
No. 6 69 70 17 No Grade III ORN Free ap Cured Alive
Table 3. Grade III osteoradionecrosis
Patient Age
(years)
Radiation
dose (Gy)
Radiation to
ORN (months)
HBOT Surgical
treatment
Outcome Survival
No. 1 83 60 192 No Free ap Free Deceased
No. 2 64 70 79 No Free ap Free Deceased
No. 3 66 60 96 Yes None Present Deceased
No. 4 64 72 6 Yes Free ap Present Deceased
unblinded randomized trial, TOBEY &
KELLY
23
concluded that HBOT signi-
cantly improved outcome of patients with
ORNwhen given at 2.0 ATA. Others have
questioned the role of HBOT. MAIER
et al.
13
in their study of patients with
severe ORN treated with surgery without
HBOTreported a success rate of 65%, and
state that they do not recommend HBOT
in the treatment of ORN. The effective-
ness o0f conservative treatment without
HBOThas been shown by WONG et al.
24
in
a retrospective study, showing 69% of
patients had lesions which resolved, sta-
bilized or improved using a conservative
or simple management plan, whilst avoid-
ing a surgical resection or HBOT. In
another retrospective cohort study invol-
ving 30 patients with Marx stage III ORN,
GAL et al.
8
concluded that microvascular
reconstruction is effective in the treat-
ment of patients with mandibular ORN
and cure can be successfully achieved
without the use of HBOT. Patients not
responding to HBOT also had signi-
cantly increased wound infection and
overall surgical complications. Their
results share similarities with the present
ndings in that 8/10 patients with grade I
ORN, 2/6 patients with grade II ORN and
2/2 patients with grade III ORN had per-
sistent wound infection and ongoing
ORN. ANNANE et al.
2
conducted a rando-
mized, placebo-controlled, double-blind
study to assess the efcacy and safety of
HBOT for overt mandibular ORN. The
trial was terminated prematurely because
of the failure to demonstrate any bene-
cial effect of HBOT over placebo in
recovery, slowing the progression of dis-
ease or pain relief.
Recent advances in the understanding
of cellular and molecular biology of radia-
tion brosis have prompted the use of
drugs in the management of ORN. The
prebrotic phase appears to be due to
vascular dysfunction
15
. The broblastic
stromal change that is seen to occur is a
result of reactive oxygen radical dereg-
ulation of broblast proliferation and
metabolism
4,21
. The broatrophic theory
has reignited interest in the use of anti-
oxidants and antibrotic drugs as an ave-
nue of treatment. ANNANE et al.
2
observed
comparable transcutaneous oxygen
saturation between irradiated and non-
irradiated skin; this challenges the con-
cept that ischaemia is the primary
mechanism for radionecrosis, favouring
the broatrophic mechanism. FUTRAN
et al.
7
tested the efcacy of pentoxiphyl-
line for radiation therapy-related soft-tis-
sue necrosis, brosis and mucosal
pain. They treated 26 patients with late
radiation complications with oral pentox-
ifyllin and found that brosis and soft-
tissue necrosis responded well, but no
effect was observed when bone was
exposed. DELANIAN et al.
4
have shown
striking regression of chronic radiother-
apy damage in a clinical trial of 43
patients treated by oral pentoxifylline
and vitamin E. The combination therapy
had reversed chronic radiation damage,
and they concluded that it should be con-
sidered as a therapeutic measure in the
management of ORN. In a more recent
study by DELANIAN et al.
5
involving 18
patients with mandibular ORN, pentoxi-
fyllin and vitamin E boosted by clodro-
nate were effective treatment for
mandibular ORN, with mucosal and bone
healing occurring over a median period of
6 months.
This small series questions the efcacy
of HBOT in the management of ORN. A
carefully constructed national or interna-
tional audit or a randomized trial would be
very useful, especially as the small num-
ber of patients makes a randomized con-
trolled trial challenging.
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Address:
Jacob DSouza
Regional Maxillofacial Unit
University Hospital Aintree
Liverpool L9 7AL
UK
Tel: +44 151 529 5287
Fax: +44 151 529 5288
E-mail: dsouzaj@mac.com
The inuence of hyperbaric oxygen on the outcome of patients treated for osteoradionecrosis 787