232

Osteoradionecrosis of the Midface and

Mandible: Pathogenesis and Management
Nima Vahidi, MD1 Thomas S. Lee, MD1 Srihari Daggumati, MD1 Tom Shokri, MD2
Weitao Wang, MD2,3 Yadranko Ducic, MD, FRCS(C), FACS2

1 Department of Otolaryngology, Virginia Commonwealth University, Address for correspondence Thomas S. Lee, MD, FACS, Department
Richmond, Virginia of Otolaryngology, Virginia Commonwealth University Hospital, 1200
2 Otolaryngology and Facial Plastic Surgery Associates, Facial Plastics, East Broad Street, 12th Floor, South Wing, Suite 313, PO Box 980146,
Fort Worth, Texas Richmond, VA 23298 (e-mail: [email protected]).
3 Department of Otolaryngology, University of Rochester, Rochester,
New York

Semin Plast Surg 2020;34:232–244.

Abstract Radiation therapy is an important and commonly used treatment modality for head and
Keywords neck cancers. Osteoradionecrosis (ORN) is a potential debilitating complication of
► osteoradionecrosis

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treatment, which most commonly affects the mandible. Management strategies are
► mandible tailored to the severity of disease. Medical management including oral rinses, irrigations,
reconstruction antibiotics, and pharmacological treatments is viable for mild-to-moderate ORN. More
► midface severe disease is best addressed with a combination of medical management and surgical
reconstruction intervention aimed at aggressively removing devitalized tissue until bleeding bone is
► maxillary encountered and reconstructing the soft tissue and bone defect. Reconstruction with
reconstruction either regional vascularized flaps or vascularized osteocutaneous free flaps in case of larger
► fibula free flap full-thickness bone defects (greater than 6 cm) or anterior mandible (medial to mental
► scapula free flap foramen) is most appropriate. Maxillary ORN complications can present with a wide range
► nasal reconstruction of functional problems and facial disfigurement. Life-threatening and time-sensitive
► hyperbaric oxygen problems should be treated first, such as skull base bone coverage or correction of severe
► PENTOCLO ectropion, to avoid blindness from exposure keratopathy. Then, less time-sensitive issues
► pentoxifylline can be addressed next, such as nasal obstruction, velopharyngeal insufficiency, and chronic
► tocopherol tearing. It may require a combination of specialists from different disciplines to address
► clodronate various issues that can arise from maxillary ORN.

Radiation Therapy of cellular reproduction and tumor cell death. Normal cells
are generally better able to withstand the effects of the
Radiation therapy is an important and commonly utilized ionizing radiation; however, even cells that survive may
treatment modality for head and neck cancers. Radiation have impaired mechanisms for the production of collagen
therapy is generally subdivided into external and internal and regulatory enzymes. This ultimately results in a progres-
(also called brachytherapy). Most head and neck cancers are sive loss of vascularity, cellularity, and tissue integrity.2,3
treated with external beam radiation therapy using high Radiated tissue is often unable to revascularize spontane-
energy photons generated by a linear accelerator.1 Mecha- ously, leading to one of the well-known complications of
nistically, the process involves targeting ionizing radiation osteoradionecrosis (ORN). One of the well-established risk
toward pathological tissue, which causes tissue damage. The factors for ORN is an increased radiation dose, usually doses
ionizing radiation creates free radicals, which cause genetic of 65 to 80 Gy, which diminishes capillary density to only 20
degradation on a cellular level and ultimately result in a loss to 40% of that of nonirradiated tissue.4 There appears to be an

Issue Theme Complications and Copyright © 2020 by Thieme Medical DOI https://doi.org/
Secondary Management and Repair in Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0040-1721759.
Head, Neck and Plastic Surgery; Guest 18th Floor, New York, NY 10001, USA ISSN 1535-2188.
Editor: Yadranko Ducic, MD, FRCS(C), Tel: +1(212) 760-0888.
FACS
 Osteoradionecrosis of the Midface and Mandible Vahidi et al. 233

increased risk of ORN when the radiation dose was  65 Gy. after 2.5 years. Trauma-related mandibular ORN shows a
Side effects of radiation therapy are generally classified as bimodal distribution, with a peak at 3 months and the other
acute or chronic in nature. Acute effects of radiation therapy peak occurring at 5 years.2 ORN of the maxilla and skull base
include mucositis, thickened secretions, mucosal infection, has also been well described and are more commonly seen in
pain, and sensory disruptions. Chronic effects typically in- combined therapies. Between 70 and 94% of ORN cases occur
clude tissue fibrosis, salivary gland dysfunction, increased within the first 3 years after radiotherapy.6
susceptibility to mucosal infection, neuropathic pain, senso- Postirradiation dental extractions are thought to be among
ry disorders, ORN, dental caries, and periodontal disease.1,5 the most common causes of ORN, with an estimated incidence
between 2 and 18% following extractions. Studies have shown
an increasing risk of ORN related to dental extractions in the
Osteoradionecrosis
first 4 to 5 years postradiation treatment. Hence, it is best to
Etiology avoid extractions during this postradiation period as much as
ORN is defined as exposed devitalized irradiated bone that possible with all necessary extractions ideally being per-
fails to heal over a period of 3 to 6 months in the absence of formed prior to the start of radiation therapy. Timing is also
local neoplastic disease. Radiographically, it is described by relatively important with respect to preirradiation dental
decreased bone density, lytic areas, cortical interruption, soft extractions. Ideally, extractions can be performed at least 3
tissue thickening, and sometimes pathological fractures to 4 weeks prior to radiation therapy, and if timing constraints
(►Fig. 1). Patients with ORN typically present with com- exist, at least 10 to 14 days should be allotted to allow recovery.
plaints of poorly controlled, persistent orofacial pain and The goal is to allow sufficient time for healing prior to the strain
chronic bone exposure, and go on to develop pathological that occurs during radiation therapy.9,10

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fractures, nonunion with chronic infection, and/or sinonasal
or orocutaneous fistulas. These pathologies may ultimately Pathogenesis
affect their swallowing, respiration, and speech function.6 The pathophysiology of ORN was first described by Marx in
ORN of the facial skeleton is one of the most devastating 1983, in which he proposed that radiation causes endarter-
complications of head and neck radiation therapy. Histori- itis and results in tissue hypoxia, hypocellularity, and hypo-
cally, it was thought to be related to radiation exposure, vascularity.11 It also reduces the proliferation of bone
trauma, and infection. More recently, identified risk factors marrow, collagen, and periosteal and endothelial cells. Radi-
for the development of ORN include the presence of dental ation-induced fibrosis theory has become a three-phase
disease, the need for preirradiation dental surgery, poor oral proposed mechanism to describe the molecular events lead-
hygiene, smoking and drinking habits, total radiation dosage ing to the clinical manifestations of the disease. The initial
(> 5,000 Gy), and the extent of original tumor size.4,7 prefibrotic phase involves the presence of endothelial cells
In a systematic review by Teng and Futran, the prevalence of with an accompanied acute inflammatory response. The
ORN was 7.4% in conventional radiation therapy, 5.1% in constitutive organized phase follows, which is defined by
intensity-modulated radiotherapy, 5.3% in concurrent che- abnormal fibroblastic activity and a loss of extracellular
mo-radiation therapy, and 5.3% in brachytherapy.6 The man- matrix organization. The final late fibroatrophic phase
dible is more commonly affected by ORN than other parts of involves remodeling of the tissues with the formation of
the facial skeleton due to differences in blood supply and fragile healed tissues at risk of reinjury. Histologically, in
anatomical structure. Mandibular ORN is encountered far ORN, there is an obvious destruction of osteocytes and an
more commonly than maxillary ORN and is thought to occur absence of osteoblasts from bone margins.12,13
in two distinct patterns. Close to 60% are considered posttrau-
matic, whereas the other 40% are thought to be spontaneous in Staging
nature.8 Spontaneous cases typically appear between 6 and Although there is currently no uniform staging system for
24 months after irradiation, with the incidence decreasing classifying ORN, several have been proposed over the years.

Fig. 1 Radiographic images of left-sided mandibular osteoradionecrosis. Left mandibular angle pathological fracture (yellow arrow) can be seen
with bony resorption and loss of cortical bone. (A) Coronal view. (B) Axial view. (C) Sagittal view.

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234 Osteoradionecrosis of the Midface and Mandible Vahidi et al.

Table 1 Different staging systems of ORN

Study Year Stages

Marx11,14 1983 Stage I Exposed alveolar bone without pathological fracture, which responds to HBO therapy
Stage II Not responsive to HBO therapy and requires sequestrectomy and saucerization
Stage III Most severe and involves full-thickness bone damage or pathological fracture and requires
resection and reconstruction with free tissue
Glanzmann 1995 Stage 1 Bone exposure without signs of infection and persisting for at least 3 mo
and Grätz16
Stage 2 Bone exposure with signs of infection or sequester and without the signs of grades 3–5
Stage 3 Bone necrosis treated with mandibular resection with a satisfactory result
Stage 4 Bone necrosis with persisting problems despite mandibular resection
Stage 5 Death from ORN
Støre and 2000 Stage 0 Mucosal defect only
Boysen17
Stage 1 Radiological evidence of necrotic bone with intact mucosa
Stage 2 Positive radiological findings with denuded bone intraorally
Stage 3 Clinically exposed radionecrotic bone, verified by imaging techniques, along with skin
fistulae and infection
Schwartz and 2002 Stage I Minimal soft tissue ulceration and limited exposed cortical bone; patients are treated with
Kagan15 conservative management

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Stage II Localized involvement of the mandibular cortex and underlying medullary bone
Stage III Full-thickness involvement of the bone, including the inferior border; pathological
fractures may be present
Notani et al18 2003 Stage I ORN confined to the alveolar bone
Stage II ORN limited to the alveolar bone and/or mandible above the level of the inferior alveolar
canal
Stage III ORN involving the mandible below the level of the inferior alveolar canal and/or skin fistula
and/or pathological fracture

Abbreviations: HBO, hyperbaric oxygen; ORN, osteoradionecrosis.

The original staging system proposed by Marx outline three tions, dental extractions will not be needed; however, occa-
stages to classify and organize disease manifestations and their sionally such circumstances may arise. If extractions are
response to hyperbaric oxygen (HBO).11,14 Since 1983, multiple necessary, they should be performed with careful soft tissue
new staging systems have been proposed each with different handling and primary wound closure. Prophylactic high-
guidelines and management strategies (►Table 1).4,11,15–18 dose broad-spectrum antibiotic coverage is important, ide-
ally continued for at least 2 weeks. Preventative HBO therapy
Prevention has also been proposed in high-risk patients.19
Over recent years, our ability to identify risk factors for ORN
and devise preventative strategies has improved. Current
Management of Osteoradionecrosis
protocols are divided into three phases: before radiation
exposure, during radiation exposure, and after radiation Medical Management
exposure. The first phase is focused on screening and initia- Early stage ORN, which is described by small areas of exposed
tion of preventative measures. During radiation therapy, the bone, is traditionally managed with conservative measures.
preventative measures are continued along with treatment These measures include thorough wound care involving oral
and counseling for acute complications. In the postradiation rinses (e.g., chlorhexidine), saline irrigations, and a strong
phase, prevention is important along with treatment of focus on oral hygiene. Acute exacerbations are managed with
chronic and late complications, and therefore close follow- broad-spectrum antibiotics and appropriate analgesia. With
up during this period is extremely important (►Table 2). conservative measures, complete resolution of ORN is esti-
Common treatment methods to combat radiation-related mated to occur in 8 to 33% of patients within 1 year.4,18 It is
side effects include daily sprays or lozenges for mucositis, important to understand the limits of medical management
chlorhexidine mouth rinse for plaque removal, pain relief and utilize appropriate adjuncts or surgical options before
rinses (e.g., viscous lidocaine or sucralfate suspension), sali- additional worsening complications arise.
vary substitutes (e.g., Biotene) for oral dryness, and trismus
prevention with mouth opening exercises. Extractions post- Hyperbaric Oxygen
radiation therapy pose a significant risk for the development HBO therapy has been described for the treatment of ORN
of ORN. Ideally, with pretreatment screenings and evalua- since the 1960s; however, its use remains controversial. The

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 Osteoradionecrosis of the Midface and Mandible Vahidi et al. 235

Table 2 Outlines preventative measures before, during, and after radiation therapy

Preradiation therapy
• Thorough assessment of dentition, periodontium, and oral hygiene (obtain radiographic information as needed)
• Extraction of nonsalvageable teeth (allow 3–4 wk for wound healing)
• Initiation of preventative measures (brushing teeth, topical fluoride application, oral rinses, trismus prevention exercises)
• Nutritional consultation (optimization of nutritional status)
During radiation therapy
• Continue preventative measures (brushing teeth, topical fluoride application, oral rinses, trismus prevention exercises,
avoiding denture use)
• Appropriate follow-up with the dental team per institutional policy
• Employ treatment measures as needed for mucositis, plaque removal, pain relief, oral dryness, and trismus
Postradiation therapy
• Close follow-up with the dental team
• Continue preventative measures (brushing teeth, topical fluoride application, oral rinses, trismus prevention exercises, wait
for 3 mo before denture use)
• Ideally no extractions needed; however, if needed, it should be carried with appropriate measures taken

purpose of HBO therapy is to increase the oxygen gradient bosis, fibrosis, and tissue necrosis. Several drugs have been
and enhance diffusion of oxygen into hypoxic tissues. The proposed in the management of ORN including pentoxifylline,

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increased oxygen content stimulates angiogenesis, collagen tocopherol, and clodronate, together referred to as PENTOCLO.
formation, and fibroblast proliferation. The increased oxygen Pentoxifylline is a methylxanthine derivative that is thought
gradient is also bactericidal and bacteriostatic, which is im- to have beneficial effects in the setting of ORN by inducing
portant in the setting of ORN as it is frequently complicated by vascular dilation and increased erythrocyte flexibility. This, in
chronic infection. turn, improves blood viscosity and flow, increasing vascularity
Historically, HBO therapy was considered an integral of affected tissues. Tocopherols are a vitamin E analog with
component of ORN prevention and treatment, but the para- antioxidant properties including inhibition of platelet aggrega-
digm has shifted in recent years.2,14 Recently a randomized, tion, production of nitric oxide in the endothelium, and pro-
placebo-controlled, double-blind study from France was duction of superoxide in immune cells. The thought is that
conducted to assess the efficacy and safety of HBO for the tocopherols scavenge reactive oxygen species that are involved
treatment of mandibular ORN. The trial was ultimately in the pathogenesis of ORN. Clodronate is a bisphosphonate that
terminated prematurely because of a failure to demonstrate inhibits bone resorption by directly acting on osteoclast activity.
any beneficial effect. Best practice guidelines from the oto- It also acts directly on osteoblasts to increase the formation of
laryngology literature in 2013 demonstrates there is no clear bone and reduce fibroblast proliferation. However, some are
evidence to suggest that HBO therapy is effective in the hesitant to use clodronate as a single or combination therapy
prevention or treatment of ORN.20 Prophylactic HBO follow- due to the mandibular ORN risk associated with bisphospho-
ing salvage surgery has also not been shown to decrease the nate use.23
rates of postoperative complications, length of hospital stays, The PENTOCLO combination as described by Delanian
or the need for additional surgical intervention.6 et al recommends initial treatment with antibiotics and
In regard to the impact of prophylactic HBO prior to dental corticosteroids for a month to control active infection,
extraction, the data have been divided. Fritz et al in a reduce inflammation, and allow for drug penetration. The
systematic review in 2010 concluded that there was no treatment regimen consisted of pentoxifylline 400 mg twice
reliable evidence to support or refute the efficacy of HBO daily plus 1,000 IU vitamin E daily and 1,600 mg of clodr-
in the prevention of postextraction ORN.21 In 2011, Nabil and onate for 5 consecutive days per week. The clodronate was
Samman found a 7% incidence of ORN after tooth extraction, alternated with 20 mg prednisone and 1,000mg ciprofloxa-
and when extraction was performed along with HBO, the cin 2 days per week. Treatment duration was dependent on
incidence was 4%. They concluded that prophylactic HBO the healing course, with a median treatment time of
may be effective in reducing the risk of ORN after postradia- 9 months.24
tion dental extractions.22 Ultimately, the utility and efficacy A combination therapy with pentoxifylline and tocoph-
of HBO therapy appear to be controversial and limited at erol has been reported to be effective in reducing progres-
best, and other adjunctive treatment modalities should be sive changes associated with ORN particularly in early stage
considered. disease. Breik et al showed a 45% response rate to the
combination therapy, demonstrating improvement in
Pentoxifylline/Tocopherol/Clodronate wound healing. It may also play a role in the conservative
Pharmacological treatments have been proposed to counteract management of patients with more advanced disease that
the molecular mechanisms associated with ORN development. refuse surgery or are nonoperative candidates. Combination
These molecular mechanisms include free radical formation, therapy with PENTOCLO has also been reported to have
endothelial dysfunction, inflammation, microvascular throm- beneficial effects; however, definitive evidence is limited for

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236 Osteoradionecrosis of the Midface and Mandible Vahidi et al.

these pharmacological modalities and further analysis is The overall goals of surgical treatment include the
needed.25 following:

• Aggressively debride mandibular bone affected by osteo-

Alternative Treatment Modalities
myelitis until bleeding bone is encountered.
Other alternative treatment modalities have been proposed for
• Cover exposed mandible as it may act as a nidus for
the treatment of ORN with the limited body of literature
intraoral microbial flora and can lead to ongoing chronic
available. Ultrasound therapy is an older treatment modality
infection.
that was first described in 1992. It was proposed to induce local
• Similarly, any exposed hardware must be replaced (if
angiogenesis and revascularization. Current literature is very
appropriate) and covered with robust vascularized tissue
limited, and thus it remains an area of continued investiga-
to remove biofilm formation on the surface of the exposed
tion.26 Recent studies have investigated the use of low-power
hardware, which may lead to an ongoing source of infec-
lasers associated with photodynamic therapy (PDT) as a
tion that may foster antimicrobial resistance to even
treatment modality for ORN. It aims to promote disinfection
intravenous antibiotic therapy.
in pathological areas by stimulating synthesis of collagen and
• In the setting of a postradiation pathological fracture,
fibroblasts. A recent retrospective study showed the combined
provide rigid fixation to achieve bony union.
use of low-power laser (Therapy XT–diode laser at 660 nm and
• In the setting of segmental bone defect, restore mandible
808 nm, DMC Group) with PDT led to remission of ORN and
continuity and premorbid occlusion with rigid fixation.
repair of mucosal damage.27 However, studies evaluating this
• Reconstruct concurrent intraoral mucosal defect and/or
treatment modality are limited in the current literature, and its
external skin defect with vascularized tissue. In the
reproducibility remains to be seen.
setting of large segmental mandibulectomy bone defects

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Other studies have mentioned both ozone and platelet-
with concurrent intraoral and/or external skin defects, a
rich fibrin as alternative therapies for ORN. Ozone is a
vascularized osteocutaneous free flap may be needed for
molecule with three atoms of oxygen, which is thought to
reconstruction.
have multiple beneficial properties including antimicrobial,
• Remove compromised dentition at the time of the definitive
analgesic, anti-inflammatory, and stimulating the circulato-
treatment surgery. If there are signs of dental infection in
ry system. It has been shown in case reports to potentially
close proximity (1 cm) to the ORN site, one should con-
possess tissue healing properties in ORN, but most authors
sider extraction of the involved tooth and aggressively
state further investigation is needed.28 Platelet-rich fibrin
debride the alveolar bone until bleeding bone edge is
has been proposed to aid in the healing process. After
encountered as it can be a source of future infection.
patients undergo surgical debridement of necrotic bone to
• Proceed with dental rehabilitation once ORN has been
achieve healthy bone margins, platelet-rich fibrin is placed in
successfully treated.
the bone defect. The platelet-rich fibrin is obtained from the
patient’s own blood and collected by centrifugation.29 Al- Salivary leakage at the site of ORN must be avoided at all
though there are many alternative therapies that have been cost as it may lead to recurrent osteomyelitis or even a free
proposed in the literature, evidence of these therapies flap loss. As such, one must be aware of the limitation of
remains limited, and further investigation is needed prior regional local flaps and potentially compromised flap vascu-
to widespread use. Furthermore, it is likely these treatment larity to tolerate salivary exposure as the wound heals. When
modalities will have limited efficacy in severe ORN cases. designing a local tissue advancement flap in the radiated
area, the advancement flap should be raised relatively thick
Surgical Management of Mandibular Osteoradionecrosis (if possible, 2–4 mm thick in either submuscular or submu-
Surgical interventions have remained a cornerstone of man- cosal plane while protecting the facial nerve innervation) to
dibular ORN treatment throughout the years. Surgical treat- further optimize distal tip flap survival. When raising an
ment is typically reserved for patients who have failed the intraoral, regional flap overlying the mandible, the flap can
aforementioned established medical therapy or if they have be raised superficial to the periosteum of the bone to tolerate
presented with severe complications of ORN. These compli- salivary exposure if it were to occur. Bone with periosteum
cations include pathological fractures of the mandible and generally tends to heal better than bone without any perios-
large soft tissue defects with exposed bone or hardware. The teum attached as vascularity to the bone itself has been
exact surgical treatment will depend on a multitude of factors decreased due to the lack of periosteum. If there is severely
and must be individualized for each patient. These factors compromised intraoral lining, it may be beneficial to consid-
include the amount of mandibular bone exposed, depth of the er an external approach with limited intraoral incision to
bony defect (partial vs. full-thickness mandibular defect), minimize the tissue burden on the intraoral incision and
location of the bone exposure along the mandible, quality of avoid a salivary leak. With the external approach to the
surrounding soft tissue that will be used for reconstruction, mandible, dissection along the bone can be performed in the
and the presence of concurrent facial skin or intraoral mucosal subperiosteal tissue plane to provide further vascular sup-
defects that will also need to be reconstructed. There is port to the intraoral lining.
currently no generalized consensus treatment algorithm for Planning of surgical incisions is extremely important
ORN. We present our treatment algorithm used by senior when working in a radiated field. Regional flap vascularity
authors (T. L. and Y. D.). (►Fig. 2) should be optimized by designing wider tissue flaps to allow

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 Osteoradionecrosis of the Midface and Mandible Vahidi et al. 237

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Fig. 2 Mandible ORN surgical treatment algorithm. (A) Partial-thickness mandibular bone defect algorithm. (B) Full-thickness mandibular bone
defect algorithm. ALT, anterolateral thigh; CTA, computed tomography angiography; FAMM, facial artery musculomucosal; FF, free flap; FFF,
forearm free flap; MMF, maxillomandibular fixation; ORN, osteoradionecrosis.

for increased vascularity to the distal tip of the flap. Distal as a sign of how robust the tissue will be during the healing
tips necrosis of a radiated regional flap can be relatively process. Aggressive soft tissue debridement is extremely
common, and this may lead to a host of complications important during the initial interventions, particularly in
including salivary fistulas. One may use distal tip bleeding the setting of chronic infections. One must avoid

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238 Osteoradionecrosis of the Midface and Mandible Vahidi et al.

overestimating the area of reliable soft tissue and, instead, air grafting and went on to achieve bony union without any plate
toward being more aggressive in soft tissue debridement to fracture. Assuming one can achieve reliable, watertight seal
ensure that any regional flap will be in contact with healthy intraorally, they recommend concurrent nonvascularized iliac
soft tissue. Additionally, if there are any signs of infection bone grafting at the time of ORIF to increase bone healing
surrounding implanted hardware, it is important to potential. They additionally noted that reconstructive plates
completely remove all compromised tissue while utilizing should be used whenever possible instead of miniplates due to
bleeding tissue edges as a healthy margin. Lastly, one may the risk of plate fracture, particularly if limited mandibular
consider the use of Dermabond (Ethicon) or a fibrin glue bone height exists.34
intraorally to create a watertight seal along the mucosal Although vascularized bone grafts are regarded as superior
incision line as an added layer of protection. in the setting of ORN, nonvascularized bone grafts may also
Small concurrent oral mucosal defects overlying the ex- play a role when there is adequate soft tissue coverage and
posed mandible can be reconstructed with vascularized local reliable mucosal closure to avoid a salivary leak. Nonvascular-
flaps, such as the facial artery musculomucosal (FAMM) flap, ized bone grafts are generally restricted to smaller mandibular
infrahyoid flap, buccal mucosal flap, or floor of mouth defects, less than 5 to 6 cm in size, and defects of the posterior
advancement flaps, among others.30–33 Due to previous mandible (lateral/posterior to mental foramen). These grafts
radiation history, one should assume poor intraoral closure are less reliable due to uneven blood supply, smaller bone
healing potential and be cautious of placing a significant stock, and limited resistance to infection in the setting of a
amount of hardware when an osseous free flap is not used or salivary leak. This can be disadvantageous if bone stock is
when insufficient soft tissue is present. needed for stabilization or dental implant placement.35 In
With respect to hardware placement, it is typically best to some cases, a bulky muscular flap, such as pectoralis major

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avoid hardware placement whenever possible as the hardware flap, can be used to wrap the reconstruction plate especially if
has a potential for both exposure and biofilm formation. With one is planning for a concurrent or a staged nonvascularized
that said, in the presence of a pathological fracture or a bone graft placement. Myocutaneous pectoralis flap with a
vascularized free flap placement, hardware placement is deepithelialized skin paddle can be used in this setting to
unavoidable and even necessary. To avoid the feared compli- minimize plate exposure. Once the patient has achieved a
cation of hardware eroding through radiated skin externally, watertight seal without a fistula, one may consider staged
placement of a well-vascularized soft tissue flap with tissue nonvascularized bone grafting using an external approach. A
bulk directly overlying the bone and hardware is recom- salivary leak on top of the nonvascularized bone graft will
mended. The radiated skin will often have severe fat atrophy, likely result in near-total graft loss and a problematic infection.
which results in extremely thin skin and becomes poorly One must be cautious about reconstruction plate place-
tolerant of a reconstruction plate. If there is regional muscle ment along the anterior mandible (medial to the mental
or relatively thick soft tissue present, the soft tissue/muscle foramen) with a full-thickness bony defect without any form
can be used to cover the bone and hardware. If there is no of bone grafting as this will likely lead to delayed plate
reliable regional muscle or soft tissue present, a de-epithe- exposure. Generally, the posterior mandible (lateral/posteri-
lialized skin flap from an osteocutaneous free flap may be used or to the mental foramen) can better tolerate plate place-
to cover the bone and hardware while the skin paddle can be ment without bony reconstruction particularly if there is
buried under the native external skin. sufficient soft tissue bulk surrounding the plate.
A pathological fracture of the mandible after radiation In the setting of severe ORN, vascularized osseous or
therapy poses a special challenge as these fractures may be osteocutaneous free flaps may be necessary. These instances
less inclined to achieve bony union than nonirradiated bone. It include those with large segmental defects (> 6 cm) or full-
appears that radiation dose that is  60 Gy is associated with a thickness bony defects along the anterior mandible (between
higher risk of pathological fracture. The most commonly the mental foramen) with or without concurrent intraoral or
involved sites include the mandibular body and angle. Kim external skin defects. Common free flaps used for mandible
et al reported successful treatment of postradiation pathologi- reconstruction include fibula, scapula, iliac crest, and radial
cal mandible fractures with open reduction and internal fixa- bone. Fibula free flap is used most widely due to relative ease
tion (ORIF) in patients presenting with severe bone deviation, with dental implant placement and favorable bone length
malocclusion, or relatively small mandibular bone height. They (►Fig. 3). Fibula free flap can provide up to 22 cm of bone
noted delayed bone healing in all ORIF patients, with bone length, which essentially allows for the reconstruction of near-
healing ranging from 5 to 19 months. Patients who underwent total mandibular defect.36 Concurrent dental implantation has
closed reduction had significantly delayed bone union occur- been described extensively in the literature and allows con-
ring after 5 years of observation. In their case series, two current dental rehabilitation. However, if the patient lacks
patients went on to have ORIF performed with miniplates adequate fibula due to vasculopathy, scapula free flap is an
and concurrent nonvascularized iliac bone grafting. These alternative option for mandibular reconstruction, although its
two patients had suffered plate fractures but went on to achieve bone length is typically limited (8–12 cm). Although not used
bony union. The authors attributed plate fractures to small as widely, using iliac crest and radial forearm free flaps have
mandibular bone height resulting in a load-bearing situation also been well established for mandible reconstruction in the
(instead of the load sharing) and delayed bone healing. One literature. Iliac crest free flap harvest in an overweight patient
patient was treated with a reconstruction plate without bone can be a challenge, and the flap may end up with excess soft

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 Osteoradionecrosis of the Midface and Mandible Vahidi et al. 239

Fig. 3 (A) The patient in ►Fig. 1 had undergone radiation therapy for mandibular squamous cell carcinoma and subsequently developed left
mandibular osteoradionecrosis. A pathological fracture can be seen upon subperiosteal dissection of the mandible bone (arrow). (B) A 7-cm
segmental mandibulectomy was performed spanning from the midbody to the midramus with resection of unreliable intraoral mucosa as well as
external skin that had gotten infected at the site of the pathologic fracture. (C) An approximately 7-cm excised mandibular segment. (D) An
osteocutaneous fibula free flap with a reconstruction plate was used for the reconstruction. Portion of the skin paddle was used for the intraoral
mucosal defect reconstruction, and the rest of the skin flap was deepithelialized and buried on top of the reconstruction plate and bone to
provide soft tissue coverage. The external skin defect was closed with neck local tissue advancement flap.

tissue bulk that may be hard to inset. Radial forearm free flaps classification schemes for describing various maxillectomy
are typically limited in terms of the amount of bone length and defects often resulting from cancer resection defects.37,38
height that can be obtained. Nonetheless, iliac crest and radial Depending on the location and size of the defect, there is a
forearm free flaps may be used successfully in select patients wide range of reconstruction options available for the max-
and depending on patient anatomy and surgeon preference. illary reconstruction addressing facial trauma or cancer

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Our treatment algorithm is outlined below (►Table 3). defects.39 Maxillary ORN complications can be diverse, and
wound healing challenges during regional or microvascular
Surgical Management of Maxillary Osteoradionecrosis free flap reconstruction present as a formidable challenge to
Maxillary ORN is relatively rare when compared with man- even the most experienced free flap reconstruction
dibular ORN. Cordeiro et al and Brown et al have created specialist.

Table 3 Summary of mandible ORN treatment recommendations by authors

Medical management
• Oral rinses (e.g., chlorhexidine) and saline irrigations
• Antibiotic therapy (broad spectrum) for acute infections
• Appropriate analgesia
• Steroids may play a role in acute inflammatory response
Hyperbaric oxygen therapy
• No clear evidence of utility in prevention or treatment; however, side effect profile is relatively low if used in select settings
PENTOCLO
• No general consensus; preliminary studies appear promising, but further investigation is needed
• Published regimen: 400 mg pentoxifylline twice a day, 1,000 IU vitamin E, and 1,600 mg clodronate for 5 consecutive days
alternating with 20 mg prednisone and 1,000 mg ciprofloxacin 2 d per week
• Treatment duration depending on clinical improvement
Surgical management
• Mild-to-moderate disease
- Aggressive bony debridement and vascularized LTA options
include buccal mucosal flap, floor of mouth advancement flap, FAMM flap, and infrahyoid flap
• Severe disease: failed conservative therapy or previous debridement with LTA
- Avoid using nonvascularized bone graft especially if mucosal closure is unreliable
- Perform aggressive bone resection including segmental mandibulectomy until healthy bleeding bone edge is encountered
- Provide adequate rigid fixation with hardware and provide adequate soft tissue coverage on top of the bone and hardware to
prevent exposure
- If the bone defect is relatively small (< 6 cm) and posterior (posterior to mental foramen), one could consider a vascularized
pedicled flap (such as pectoralis flap) with reconstruction plate placement with staged nonvascularized bone graft (iliac bone
graft once the oral lining has sealed up). However, reconstruction plates in this setting may cause a delayed complication of
either intraoral or external exposure. Wrapping the pectoralis muscle around the plate may minimize the risk of plate exposure.
- If the bone defect is relatively large (> 6 cm) and/or involves anterior mandible (anterior to mental foramen), typically a
vascularized bone flap will be necessary to span the bone defect while rigid fixation is performed with a reconstruction plate.
Osseous or osteocutaneous fibula or scapula free flap can be used. Skin from the free flap can be used to reconstruct intraoral
and/or concurrent external skin defect, whereas deepithelialized portion of the skin flaps can be used for coverage for hardware
and bone.

Abbreviations: FAMM, facial artery musculomucosal; LTA, local tissue advancement; ORN, osteoradionecrosis; PENTOCLO, pentoxifylline/tocopherol
(vitamin E)/clodronate.

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240 Osteoradionecrosis of the Midface and Mandible Vahidi et al.

Postradiation-related complications of the maxilla can be fistulas resulting in adjacent bony exposure and unnatural
diverse and can present with challenging wound healing issues communication along the orbital bone, anterior skull base, or
as well as irreversible scar contracture issues that can signifi- maxillary bone. The following complications are also rela-
cantly distort normal skin and cartilage and result in severely tively common: (1) VPI resulting from a palatal defect in a
compromised function and facial disfigurement. The multi- situation where a flap placed intraorally failed to heal with
tude of functional problems can involve the orbit, sinus, nasal an air and watertight seal along the entire palate, (2) nasal
airway, skull base, and intraoral region. Depending on the obstruction and VPI with a concurrent large septal perfora-
location involved, these patients may present with a combi- tion and palatal defect, (3) nasal obstruction from severe
nation of problems that may require a combination of different twisting of the nasal tip or total collapse of the nasal
specialists (skull base specialist, rhinologist, oculoplastic sur- cartilage, or nasal vestibular scarring from asymmetric radi-
geon, rhinoplasty specialist, microvascular surgeon). ation effect of treating only one side of the face (ipsilateral to
When a maxillary ORN patient presents with a combina- the tumor side), (4) massive nasal cutaneous fistula resulting
tion of problems, it is important to prioritize what needs to from postradiation full-thickness tissue breakdown along
be addressed first and stage future surgeries to address lesser the Weber Fergusson incision/external lateral rhinotomy
important issues at a later point. For example, if a patient incision, and (5) orbital or skull base bony exposure.
presents with a sinonasal fistula at the site of Weber Fergu- Management of radiation-related complications is a chal-
son incision after getting radiated to the ipsilateral maxilla, lenging process. The treatment of oronasal fistulas and VPI is
such a patient may present with a host of problems including one such example that depends on a multitude of factors
(1) sinonasal fistula, (2) localized sinusitis, (3) nasal obstruc- including palatal defect size and severity of the functional
tion as a result of severe contracture of the nasal tip toward deficit. Depending on the reliability of the local tissue a

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the side of the radiation, (4) osteomyelitis along the skull regional flap, such as a FAMM flap, may be a consideration.
base or orbital bone if exposed, (5) diplopia if there is an issue Alternatively, one may choose to follow cleft palate recon-
with the orbital floor reconstruction (infected or exposed struction principles with the understanding that radiated
orbital floor hardware), (6) exposure keratopathy from se- mucosa may poorly tolerate extensive dissection. Regardless
vere ectropion, resulting from lower eyelid scar contracture, of the reconstructive option chosen, in general, it is best to
(7) chronic tearing due to loss of lacrimal duct, and (8) palatal avoid relying heavily on radiated, local skin flaps and raise
defect resulting in salivary leak and velopharyngeal insuffi- thicker flaps to optimize vascularity as the radiated tissue
ciency (VPI). can be notoriously unreliable. It is typically safer to recruit
In general, first priority should be given to addressing life- additional nonirradiated vascularized tissue for the recon-
threatening or time-sensitive issues such as surgical treatment struction. In the case of a palatal fistula, another treatment
of the skull base osteomyelitis by debriding the dead bone and option would be to consider a customized obturator, which
covering the exposed bone with a vascularized tissue. Preserv- can obliterate the fistula with the added benefit of concur-
ing vision should receive a special priority by surgically rent dental rehabilitation.
treating significant exposure keratopathy with lower eyelid Complications related to nasal obstruction, vestibular ste-
reconstruction and correcting the severe ectropion. Once life- nosis, and cosmetic nasal deformities secondary to radiation
threatening and time-sensitive problems are addressed first, side effects can be extremely challenging to address for even the
the next set of surgeries will focus on improving “lesser” most experienced rhinoplasty surgeons. Often times, achieving
important functional problems such as performing dacryo- perfect nasal symmetry can be extremely challenging as the
cystorhinostomy to address chronic tearing or addressing the radiated side will behave differently than the nonirradiated
nasal obstruction and disfigurement caused by severe vestib- side, and the radiated side will have severely compromised
ular stenosis and twisting of the nasal tip. nasal skin envelope as well as nasal cartilage atrophy and loss of
Postradiation-related complications may not appear for 3 to structural support (►Fig. 4). As such, proper patient counseling
6 months or up to several years after the completion of and management of their expectations are important. Surgi-
radiation therapy. During the first 3 to 6 months after radiation cally, attempts should be made to restore lost nasal cartilage
therapy, one must be cautious of raising skin flaps or making structural support with placement of large spanning lateral
incisions in the radiated field, as the skin flaps may poorly strut and columellar strut grafts. To address severely contracted
tolerate these maneuvers and may result in skin flap failure. nasal skin flap, carefully planned local tissue advancement skin
Seniors authors generally delay operating in a radiated field for flap may be needed to provide sufficient skin envelope to cover
at least 6 months postradiation to minimize the risk of poor the autogenous cartilage grafts on the radiated skin flap side. In
wound healing and distal tip skin flap failure. The precise some cases, a melolabial fold flap, a paramedian forehead flap
surgical plan for these patients should be guided by both the (PMFF), or even a radial forearm free flap may be required
anatomical/cosmetic and functional deficits that may exist. depending on the size of the nasal skin defect and concurrent
Additionally, it is important to medically optimize these involvement of the upper lip or medial cheek skin defect. Lastly,
patients prior to undertaking surgical interventions. This radiated nasal skin flap may not tolerate significant separation
includes restoring normal thyroid function and correcting from the underlying structure, as often is done in an open
nutritional deficits that may exist. rhinoplasty approach, and may require a creative incision
Some of the common postradiation-related issues that are approach to optimize skin flap vascularity. It may take a
encountered include oral cutaneous or sinonasal cutaneous multistage surgical approach to achieve the desired result.

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 Osteoradionecrosis of the Midface and Mandible Vahidi et al. 241

Fig. 4 (A) A patient with a right-sided maxillary squamous cell carcinoma underwent medial maxillectomy and partial rhinectomy of the entire
right ala and right nasal wall. During the initial resection, the patient underwent rib cartilage grafting and melolabial flap surgery to address the
partial rhinectomy defect. However, after postoperative radiation therapy, the patient developed osteoradionecrosis, which was likely related to
an odontogenic infection arising from the ipsilateral maxillary canine and incisor. This led to extensive maxillary bone osteomyelitis and a
cutaneous fistula formation with a communication into the nasal cavity as well as the oral cavity through a defect along the upper lip region. The
severe twisting of the nasal tip is typical of unilateral radiation therapy. Attempts at using medial cheek advancement and supraclavicular skin
flap led to a persistent fistula formation and ongoing infection. (B) The patient eventually required a radial forearm free flap (arrow) to provide

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sufficient soft tissue bulk to cover the maxillary bone and to provide a large skin envelope to reconstruct the nasal ala and upper lip defect. (C)
The nasal tip required extensive rib cartilage grafting with large lateral strut grafts and a columellar strut graft to correct the severe nasal tip
twisting. The patient will undergo staged vestibular stenosis repair of the right side to connect to the right nasal cavity at a later time once the
radial forearm free flap has had a chance to atrophy and heal for at least 6 months.

Another radiation-related nasal deformity we encounter ing a large musculocutaneous free flap in the orbital socket
relatively commonly is associated with the use of an external at the time of the initial resection with the expectation that
lateral rhinotomy incision or Weber Ferguson approach. In radiation therapy will result in significant flap volume loss.
the setting of radiation, surgeons should be aware of the poor Despite appropriate preventative precautions, orbital exen-
wound healing capability of these incisions and the potential teration poses a particular reconstructive challenge as these
for large nasocutaneous fistulas to occur along the incision patients can develop a fistula to the sinus or the anterior
after the radiation therapy in a delayed fashion. Therefore, it skull base. To seal off the fistula, a secondary free flap may
is the senior authors’ opinion that lateral rhinotomy or be needed for additional volume. Alternatively, local re-
Weber Ferguson incisions should be avoided whenever gional flaps may provide adequate reconstructive options in
possible if postoperative radiation is required. Instead, a situations when a free flap is deemed too big for the size of
midfacial degloving approach can be used for access to the the defect. We have had success reconstructing such orbital
entire midface with less likelihood of fistula formation along fistula postradiation using a combination of pericranial flap
the incision. Once a nasal fistula has developed along the and a temporalis muscle flap. The pericranial flap is used to
previous lateral rhinotomy incision, one should consider line the anterior skull base and orbital roof once the
reconstruction from both a cosmetic standpoint and a func- devitalized bone has been drilled away. The temporalis
tional one. The PMFF can be a versatile option for the muscle flap is then raised and tunneled into the orbital
reconstruction of nasocutaneous defects. To properly seal socket by making a large bony opening immediately poste-
off the fistula, the PMFF should be raised with an underlying rior to the lateral orbital rim and removing the lateral
pericranial flap attached at the base to increase the flap orbital wall. One may also consider creating an osteoplastic
thickness to provide an additional layer of vascularity bone flap involving the lateral orbital rim to improve
(►Fig. 5). If the PMFF is inadequate or too small for the exposure while drilling along the lateral orbital wall, al-
reconstruction of the defect, utilizing a radial forearm free though that is not always necessary. Any skin defects that
flap may provide an ideal reconstruction option as it pro- arise can be closed with either local tissue advancement or
vides relatively thin, nonirradiated, vascularized donor skin grafting depending on local factors and the size of the
tissue. skin defect (►Fig. 6).
During maxillectomy, orbital exenteration is performed The exact type of flap reconstruction required for max-
if there is gross cancer invasion of the orbital content. illa depends largely on the amount of full-thickness bone or
Postoperatively, the orbit will be covered with radiation soft tissue flap that will need to be reconstructed. Coskun-
treatment in these malignant cancer patients. The recon- firat et al published a case series of microvascular recon-
struction of the orbit should be able to tolerate a full dose of structive options for maxillary defects. They utilized a
radiation therapy, and the underlying orbital bone and combination of flap options including anterolateral thigh,
anterior skull base bone should remain covered under a radial forearm, rectus femoris musculocutaneous, and
vascularized flap. In these situations, we recommend plac- supracondylar chimeric flaps. They concluded the

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242 Osteoradionecrosis of the Midface and Mandible Vahidi et al.

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Fig. 5 (A) A patient initially presented with an advanced maxillary squamous cell carcinoma that required left maxillectomy including the orbital
floor and unilateral palate resection. The patient had the resection performed with a Weber Ferguson incision. At that time, the patient had a
scapula tip free flap for the palate and anterior maxilla reconstruction, and the orbital floor was reconstructed with an orbital floor implant. At
6 months postradiation, the patient presented with a large nasocutaneous fistula at the site of Weber Ferguson incision that eventually enlarged
further and exposed the orbital floor implant. Nasal tip is severely twisted as typically seen with unilateral radiation therapy. The previously
placed scapula flap along the palate and anterior maxilla was in good condition and uninvolved. (B) To address the nasocutaneous fistula (arrow)
and severe ectropion resulting from radiation-induced skin contracture, a medial cheek skin flap (star) was raised thick and pedicled medially to
be used as the inner nasal lining. (C) The patient underwent an orbital floor implant removal, and an iliac bone graft was used to recreate the
orbital floor (triangle). A paramedian forehead flap (square) was used to provide a second layer closure to seal off the nasocutaneous fistula, while
also reconstructing the missing left nasal sidewall and ala. (D) The fistula had sealed off, and the patient had undergone paramedian forehead
flap division surgery around 6 weeks later. After the division surgery, the patient unfortunately had multiple medical issues including sudden
hypothyroidism, and the patient presented with a recurrence of the fistula at the same site along the previous lateral rhinotomy incision
approximately 3 months after the division. The paramedian forehead flap did survive and remained as the left nasal ala. (E) Once his thyroid
function had returned to normal, the patient underwent a radial forearm free flap reconstruction, which was used to provide the inner nasal
lining and the medial cheek and lower eyelid skin to successfully seal off the nasal fistula without recurrence. Arrow, fistula; star, cheek
advancement flap for nasal lining; triangle, Iliac bone graft for orbital floor reconstruction; square, paramedian forehead flap; circle. radial
forearm free flap.

anterolateral thigh was the most versatile option for oblit- common belief, scapular free flaps can tolerate osteotomies
erating large dead space and for soft tissue defect recon- by maintaining the periosteal attachments and also allows
struction without needing bone reconstruction.40 However, dental implant placement depending on the bone thickness.
if the anterior arch of the maxillary bone along the hard Similarly, a fibular free flap has also been utilized for the
palate is involved with a full-thickness bone defect (be- reconstruction of the bony maxilla. The fibula provides
tween the canines) and if bony reconstruction is desired to several advantages including a long vascular pedicle, which
maintain proper skeletal support to prevent irreversible may be preferable in patients with depleted cervical donor
midfacial skin contracture that can occur with radiation vessels for optimal vessel reach, and easier dental implan-
or for dental rehabilitation, the scapular free flap may be an tation due to its thicker bone when compared with a
ideal option as reported by Miles and Gilbert.41 Contrary to scapula flap.42

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 Osteoradionecrosis of the Midface and Mandible Vahidi et al. 243

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Fig. 6 (A) A patient initially presented with an aggressive, mucoepidermoid carcinoma of the lacrimal duct with gross skin and ipsilateral eye
involvement. The patient underwent medial maxillectomy with orbital exenteration. At that time, osteocutaneous radial forearm free flap was
used to restore the resected medial buttress and to provide skin coverage along the orbit and medial cheek. Four years after completion of
postoperative radiation, the patient presented with a fistula in the orbital region. The fistula had communication to the sinus and the orbital roof.
(B) The patient underwent a bicoronal incision approach to expose the orbital roof. The orbital roof and anterior skull base were gently drilled
down until bleeding bone was encountered. A large pericranial flap was developed based on the contralateral blood supply and draped along the
exposed orbital roof and anterior skull base bone. (C) Temporalis muscle flap was tunneled into the orbit by creating a large opening immediately
behind the lateral orbital rim. A suction can be seen traversing the large bone opening. (D,E) The temporalis muscle was placed on top of the
pericranial flap and was used to obliterate the dead space. (F) To address the temporal hallowing, composite abdominal fat graft was placed
along the temporalis flap donor site to correct the volume defect. (G) Small remaining skin defect was addressed by skin grafting on top of the
underlying pericranial/temporalis muscle flap. (H) The patient healed without fistula recurrence and shows no significant temporal hallowing.
Star, pericranial flap; square, temporalis flap; arrow, abdominal fat graft; circle, lateral orbital rim.

Funding 5 Sroussi HY, Epstein JB, Bensadoun RJ, et al. Common oral com-
None. plications of head and neck cancer radiation therapy: mucositis,
infections, saliva change, fibrosis, sensory dysfunctions, dental
caries, periodontal disease, and osteoradionecrosis. Cancer Med
Conflict of Interest
2017;6(12):2918–2931
None declared. 6 Teng MS, Futran ND. Osteoradionecrosis of the mandible. Curr
Opin Otolaryngol Head Neck Surg 2005;13(04):217–221
7 Nabil S, Samman N. Risk factors for osteoradionecrosis after head
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