TITLE: Osteoradionecrosis of the Mandible
SOURCE: Grand Rounds Presentation, Dept of Otolaryngology, UTMB, Galveston, Texas
DATE: December 10, 1997
RESIDENT PHYSICIAN: James Grant, M.D.
FACULTY PHYSICIAN: Francis B. Quinn, Jr., M.D.
SERIES EDITOR: Francis B. Quinn, Jr., M.D.

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"This material was prepared by resident physicians in partial fulfillment of educational requirements established for the Postgraduate Training Program of the UTMB Department of Otolaryngology/Head and Neck Surgery and was not intended for clinical use in its present form. It was prepared for the purpose of stimulating group discussion in a conference setting. No warranties, either express or implied, are made with respect to its accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of members of the UTMB faculty and should not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion."


For the management of head and neck neoplasms, surgery and radiation therapy are frequently employed treatment modalities. There are essentially three basic means for the therapeutic delivery of the required dose: (1) external beam – radiation administered through planned portals to a specified anatomical area, (2) interstitial brachytherapy – radioisotopes within a tube implanted into tissue, and (3) intracavitary brachytherapy – radioisotopes contained in an applicator that is placed within a body lumen.[1] At a cellular level, the most common mode of cell death or damage is through its damage inflicted on DNA, specifically by the interaction radiation induced formation of hydroxyl free radicals. The effect of the radiation injury on the DNA is manifest when the cell attempts to undergo mitotic division. While damage to other organelles, the cellular membrane, and microtubules also occurs, they are generally more resistant to the effects of radiation injury. The radiosensitivity of the particular cell is defined by certain characteristics, such as the degree to which the targeted cell is ultimately able to repair the DNA damage as well as the cell population’s ability to regenerate or repopulate in response to the damaged target cells around them.[2] The radiosensitivity is clearly dependent on the stage of the cell cycle that the cell is in at the particular time of radiation exposure.

In regards to actual radiation injury, there is an early and late phase, relating to the targeted pathology as well as the surrounding normal tissue. Early radiation injury is secondary to depletion of those cells that typically divide frequently. While carcinomas usually behave like early responding tissues (frequently dividing), the epithelial cells within the treatment field are also, evidenced by commonly encountered mucositis or dermatitis as an relatively acute clinical soft tissue adverse side effect.[3] Late radiation injury occurs in those tissues that proliferate slowly or not at all, where the effect is not clinically manifest until far later, generally from microvascular damage in addition to the gradual depletion of these infrequently dividing cells.

The concepts of total radiation dose, the dose per fraction, and the time over which the total dose is given have definite implications for the clinical manifestations of the injuries induced in the early and late responding tissues. The most important factor affecting the risk of injuring the early responding tissues has been defined as in terms of the overall time of treatment.[4] In response to the cellular death as mitosis is attempted, a homeostatic mechanism occurs which then stimulates an overall accelerated rate of repopulation of this particular faction; therefore, by using accelerated treatment schedules (i.e. twice daily fractionation) there is diminished opportunity for repopulation.[5] In short, the probability of injury to the early responding tissues (i.e. cancerous cells) is increased through a decreased overall treatment time. Unfortunately, this reduced opportunity of repopulation affects the normal tissue present within the treatment field. In contrast, the most important factor affecting the risk of injuring late responding tissues has been determined to be the actual individual fraction dose.[6] It has been shown that at the lower fraction doses, late responding tissue survives more than the early responding tissue. At higher fraction doses, however, the surviving portion of late responding tissue is found to drop off much more rapidly than the early responding tissue. Therefore, damage to late responding tissue is increased in radiation treatment plans using a higher fractionation dose and decreases in the those regimens using a lower fractionation dose.

Histologically, the effects of radiation on bone and the adjacent soft tissue have been well studied and documented in the literature. In general, there are six histopathological changes that occur temporally in relationship to radiation exposure. This includes hyperemia, inflammation (endarteritis), thrombosis, cellular loss, hypovascularity, and progressive fibrosis. Fibroblast populations undergo not only total cellular depletion in response to radiation exposure but show a reduced activity or aberrant ability to intracellularly produce and extrude collagen into the surrounding tissue. Equally striking is the histological evidence of progressive obliteration of tissue vascular system, ultimately leading to a markedly hypoxic, hypovascular tissue bed.[7] Specifically in bone, there is an imbalance in the radiosensitivity of osteocytes, with osteoblasts depleted far greater than osteoclasts with a given radiation dose. This leaves the compromised bone with an environment favoring oseoclastic resorption of bone with a reduced bone rebuilding potential. In addition, the overall progressive endarteritis markedly reduces blood flow through the Haversian and Volkmann’s canals, leading to a pathological reduction of bone density.[8] The bone and surrounding tissue in the irradiated field come to exist in a significantly challenged metabolic state.

Through an understanding the adverse side effects of radiation therapy on the surrounding normal tissues, the pathophysiology of osteoradionecrosis can be explored. As the primary osseous complication arising from radiation injury, osteoradionecrosis has clinically been defined in literature as irradiated bone that has failed to heal in three months; more specifically, it is best described as a slow-healing radiation induced ischemic necrosis of the bone with associated soft tissue necrosis of variable extent occurring in the absence of tumor necrosis, recurrence, or metastatic disease.[9] In older literature, the lack of a well elucidated histopathological changes of the bone and soft tissue alluded to a different theory as to the etiology of osteoradionecrosis. Microbiologic sepsis rather than a true wound healing process was given priority in the pathophysiological events that occurred in osteoradionecrosis. In an article published in 1970 by Meyer, he presented the unrefutable triad of radiation, trauma, and infection in the development of osteoradionecrosis.[10] The paper documents clearly that in the irradiated bone there must be a traumatic event that propagates an ingress of microorganisms into the wound, with the traumatic events defined as tooth extraction, inadequate alveolectomies leaving sharp bony fragments, denture wearing, and tissue biopsies.

With the advent of a defining traumatic event or situation, an overwhelming, severe radiation osteomyelitis becomes manifest, spreading easily through the bone which at this time has essentially lost its ability to normally resist and wall off this bacterial infection.[12] Marx argues that this article fails to adequately demonstrate this claim of bacterial invasion in compromised bone, stating that "he (Meyer) did not demonstrate through cultures or tissue sections such a spread of osteomyelitis and microorganisms throughout the bone; neither did he demonstrate septic destruction in such avascular tissue, which can not mount an inflammatory response or wall off microorganisms".[13] In addition, those cases of osteoradionecrosis in which there is no definable traumatic event, so called "spontaneous: osteoradionecrosis, as well as the indirect evidence of poor response to treatment with antibiotic therapy casts doubt on this proposed series of events. It is Marx’ s contention that osteoradionecrosis is related to the cumulative tissue damage induced by radiation rather than to trauma or the ingress of microorganisms in the compromised tissue.[14]

In Marx’ s landmark study on the pathophysiology of osteoradionecrosis, he presented results which illustrated the following points – (1) not all cases of osteoradionecrosis could be correlated with a traumatic event (35% of the cases studied were not associated with an inciting event); (2) those "spontaneous" osteoradionecrosis cases were typically associated with significantly higher total radiation doses and more often associated with combination implant and external beam regimen; and (3) the microbial study did not demonstrate microorganisms in deep bone samples from ORN samples on culture or tissue sections, only superficial, surface contamination.[15] These results have been duplicated in several independent studies and has given credence to the principle that osteoradionecrosis is not a primary infection of bone, rather a complex metabolic and tissue homeostatic deficiency seen in this hypocellular, hypovascular, and hypoxic tissue. He refers to this as the three "H" principle.

With radiation induced changes in the tissue resulting in hypocellularity, hypovascularity, and overall hypoxia, this tissue has a markedly decreased ability to initiate repair. In fact, the area becomes so compromised that even the routine remodeling and repair that occurs continuously in normal tissue becomes markedly reduced. There are definite limitations for this tissue to meet even the most basic metabolic demands imposed on it and when forced to increase these repair requirements associated with traumatic event, for example dental extraction, a chronic, non-healing wound is easily produced. The classic sequence of radiation, trauma, and ensuing infection, therefore, is now replaced with a more current view that directly reflects the underlying metabolic and cellular changes regarded as basic to the pathophysiology of ORN. This sequence is (1) radiation, (2) hypoxic-hypovascular-hypocellular tissue, (3) tissue breakdown in which cellular death and collagen lysis exceed synthesis and cellular replication, and (4) finally, the progression to non- healing wound in which the energy, oxygen, and metabolic demands clearly exceed the supply.[15] The basic conclusions in his landmark article, in summary, is that (1) osteoradionecrosis is not a primary infection of bone, rather a homeostatic imbalance, (2) microorganisms play surface contaminant role only, and (3) trauma does not necessarily need to be an inciting factor.

With the principle of hypocellularity, hypovascularity, and hypocellularity in mind for the pathophysiology of osteoradionecrosis, there are a few factors that place the mandible at an increased risk when compared to other bones in the craniofacial skeleton. In general terms, a bone with a more tenuous blood supply that is more mechanically stressed is much more susceptible to the development of osteoradionecrosis. The craniofacial skeleton receives its blood supply in three distinct manners: vessels that enter the bone via direct muscular attachments, periosteal perforators, and intramedullary vessels. Anatomically, the vast majority of the bones of the craniofacial skeleton receive its blood supply through nutrient vessels from the periosteum and muscular attachments; in contrast, these bones, with the mandible as an exception, generally do not have an intramedullary blood supply. In fact, the mandible has different dominant blood supply according to various regions in the bone itself. The posterior segment of the mandible (condyle process and neck, coronoid, angle, and upper ramus) receives most of its vastly redundant blood supply from the surrounding musculature, either from direct muscular attachments or through muscular perforators penetrating the periosteum.[17]

Because of this redundancy, the posterior segment is typically less susceptible to radiation induced ischemia. In contrast, the anterior segment of the mandible does not have this prominence of nutrient vessels supplied through the muscular attachments. Injection studies in the mandible have shown that the primary nutrient source for the body, parasymphaseal, and symphaseal regions is through an intramedullary source, the inferior alveolar artery.[18] There is a second, far less significant blood supply from small periosteal perforators in this region.[19] In a study by Bras, et. al. on mandible resected during the course of treatment for osteoradionecrosis, radiation induced obliteration of the inferior alveolar artery was consistently found and was felt to be a dominant factors in the onset of the disease.[20]

The study further detailed that revascularization or collateral blood flow from branches of the facial artery are prevented from nourishing the ischemic mandible because of concomitant radiation induced intimal fibrosis of the small periosteal vessels as well as the direct fibrotic changes to the overlying periosteum itself.[21] When compared to irradiated mandibles that were not clinically characterized as osteoradionecrosis, there was significantly less fibrotic response with only partial obliteration of the supplying inferior alveolar artery.[22]

There are several significant factors in the head and neck irradiated patient that predisposes or are associated with the occurrence of osteoradionecrosis of the mandible. The total dose of radiation therapy, has been found to correlate with increased risks of developing osteoradionecrosis. Based on combined institution’s clinical experience reported in the literature, there appears to be direct relationship between the total dose and the incidence of osteoradionecrosis, with a threshold of 5000 cGy. Total doses less than 5000 cGy have a reported no to minimal risk. In contrast, when the total radiation dose is 7000 cGy or greater, there is 10 times the relative risk of osteoradionecrosis when compared to the group receiving less than 5000 cGy.[23] In addition, the mechanism of radiation delivery can significantly impact the development and severity of necrosis, with brachytherapy implants having the greatest relative risk in combination with external beam exposures of 6500 cGy (estimates ranging from 12 - 15 times).[24]

In an by Kuluth et.al. on the factors contributing to this disease, they found there was statistically significant incidence of osteoradionecrosis in those that patients with more advanced tumors (stage III or IV), recurrent tumors, tumors involving the tongue, retromolar trigone, and floor of mouth, and clearly with tumors invading bone.[25] It is suggested that there is a higher incidence of osteoradionecrosis in those advanced, larger lesions as there is typically a multimodality approach, with surgical intervention being in part responsible for a diminished blood supply to the area. Other factors associated with an increased incidence of ORN includes poor nutritional status, continued use of alcohol and tobacco, use of chemotherapy in conjunction with radiation therapy and/or surgery, volume of mandible within the radiation field, mandibulotomies within the field, and individual patient sensitivity.

Finally, poor dental status is a particularly significant factor, especially in considering the unfavorable environment of radiation induced xerostomia which further predisposes to dental caries and periodontal infection.[25] Pre-radiation prophylactic dental extractions are felt to be one of the cornerstones in preventing osteoradionecrosis, especially by allowing the avoidance of post-radiation dental manipulations that literature supports as a dominant risk factor.

Because the presence of carious and periodontally compromised teeth in the irradiated mandible has often been associated with osteoradionecrosis, the current school of thought is that extractions of grossly carious, periodontally "hopeless," or those teeth deemed to have poor prognosis for retention beyond twelve months should be removed prior to the initiation of radiation therapy.[27] Through a prophylactic extraction of poor teeth prior to radiation therapy, dental manipulations can generally be avoided in the post irradiation period. With the basis in the hypocellular-hypovascular-hypothesis theory in the pathophysiology of osteoradionecrosis, it has felt that extracting teeth in an irradiated field presents too great of a metabolic demand on the compromised tissue too allow for adequate wound healing. The irradiated mandible is felt to be at a significant risk of osteoradionecrosis if dental extractions are performed at this time. Different institutions give widely varying reports on the incidence of ORN when comparing pre and post radiation treatment dental extractions. Review of data published in the last decade in an analysis, however, estimate that there is twice the risk of developing osteoradionecrosis from post irradiation dental extraction.[28]

Of note, some institutions, albeit the vast minority, report no significant difference between these two groups and therefore question the merits of prophylactic tooth removal. For pre-treatment extractions, it has been recommended to minimize trauma by conservatively reflecting a mucoperiosteal flap, forcep extraction of the tooth, meticulous alveolectomy to reduce sharp bony fragments, and to close the wound under minimal tension.[29] The post surgical healing time prior to starting radiation treatment has been under debate where some authors provide a 10 day healing period while some authors are strong advocates for longer. In an article by Marx and Johnson, they compared the incidence of osteoradionecrosis in pre-treatment tooth removal patients to the timing of the surgical insult. From their collected data, they found that most of the osteoradionecrosis that developed was in those patents in which treatment was begun within the first two weeks post extraction, where there was found to be an inflection point at 12 - 15 days showing a reduced incidence to a moderate level.[30] They found no cases of osteoradionecrosis, however, when the tissue was allowed to heal for 21 days or more.[31]

While dental manipulation in an irradiated bone is best not performed, as evidenced by the drive for pretreatment prophylactic removal, dentulous patients with dental disease may require surgical intervention. Extreme attention in avoiding reflection of the periosteum and conservative alveoloplasty is advocated. In a prospective study by Marx and Johnson, the prevention of osteoradionecrosis in the high risk irradiated patient requiring tooth extraction was investigated by using penicillin versus hyperbaric oxygen therapy as a prophylactic measure. One study group received a ten day treatment period with oral penicillin in addition to a single preoperative dose of intravenous aqueous penicillin while the second study group received no antibiotic but underwent a twenty pre-operative and ten post-operative hyperbaric oxygen exposures (100% humidified oxygen / 2.4 atmospheres absolute pressure / 90 minutes per exposure).[32] The results of this particular study showed a six-fold incidence of osteoradionecrosis at the socket site in the group receiving the antibiotic. The conclusion of this study was that hyperbaric oxygen therapy in this particular clinical situation may be extremely beneficial as a preventative. Additionally, the success of hyperbaric oxygen when compared to the use of antibiotics, according to the authors, further supports the view that the actual role of microorganisms in the pathogenic development of osteoradionecrosis should be minimized. It is the impact of the diminished cellular and vascular components of the bone and soft tissue that should be emphasized as the dominant pathologic change leading to the chronic wound problem. Through the use of HBO, the cellular and vascular problems are tackled. The mechanism of hyperbaric oxygen in reducing the risk of osteoradionecrosis is by ultimately stimulating tissue angiogenisis in this hypovascular irradiated tissue through intermittent high oxygen tissue levels.[33] It has been documented that irradiated tissue has a low PO2 of 5 - 15 mm Hg; however, when this hypoxic tissue’s PO2 is raised intermittently to even a minimum of 20 - 35 mm Hg, fibroblasts are stimulated to proliferate and deposit collagen.[34]. Normally, the hypoxic conditions do not allow the remaining fibroblasts extrude their intracellular procollagen; however, with the intermittent hyperoxic conditions, a favorable environment exists for the collagen to be laid into the tissue. Along this carefully formed collagenous framework, capillary proliferation occurs gradually increasing the overall vascularity in the tissue.[35] This, in turn, allows for further fibroblast proliferation and activity.

Under this condition, the tissue is more resilient to surgical insult, able to meet the metabolic demands of wound healing. Regarding the amount of hyperbaric oxygen exposure required to reduce the risk of osteoradionecrosis following dental extraction, this has been studied by following a characteristic tissue response to hyperbaric oxygen exposure. Indirect evidence of increased density of vascular tissue is seen after only eight sessions by showing an elevation of the transcutaneous oxygen tensions in the tissue from pre-treatment levels.[36] At 20 sessions, however, the transcutaneous oxygen tension plateaus at approximately 80 - 85% to the non-irradiated region and does not appear to significantly change with further treatment.[37] Interestingly, patients followed years after hyperbaric oxygen exposure show evidence the vascular density regressed as the transcutaneous oxygen tension remained at or within 90% of the values recorded directly after completing hyperbaric oxygen treatment. The rationale for the 10 post extraction sessions in this preventative protocol is to reduce wound dehiscence through the promotion of collagen production at the incision lines.[38]

While the merits of this hyperbaric oxygen therapy protocol in high risk patients undergoing dental extractions are extolled in this landmark study by Marx, et al, this HBO protocol has been attacked by a few authors. It has been stated that hyperbarics is not absolute in the prevention of osteoradionecrosis and that the overall cost of preventative treatment is overwhelming in considering experience that the majority of the patients undergoing post radiation therapy dental extractions do not develop osteoradionecrosis. This, in part, reflects the lower incidence of ORN in dental extractions in the irradiated patient in these clinical studies.

The actual clinical definition of osteoradionecrosis is exposed, necrotic bone typically associated with ulcerated or necrotic surrounding soft tissue which persists for greater than three months in an area that had been previously irradiated. This occurs in the absence of local primary tumor necrosis, recurrence, or metastatic disease. This bone death may occur shortly after radiation injury or years later. There are three types of osteoradionecrosis, as described by Marx. Type I develops shortly after radiation therapy and is secondary to the synergistic effects of surgical trauma and radiation closely coupled in time leading to devascularization of the mandible.[39] Type II develops years after the completion of radiation therapy and follows a distinct traumatic event, representing the progressive endarteritis and vascular occlusion of the nutrient vessels in the bone, periosteum, and surrounding soft tissue with the absolute inability for wound repair.[40]

Finally, type III is the type of osteoradionecrosis which occurs spontaneously without a defining preceding traumatic event and usually manifests between 6 months and three years after radiation.[41] As noted from the occurrence of osteoradionecrosis several years after the completion of radiation therapy, the dogma that irradiated tissue repairs itself is incorrect. It remains compromised for the life of the patient. Common symptoms associated with osteoradionecrosis are pain, halitosis, and food impaction in the area of the lesion. Examination will reveal the exposed bone with concomitant soft tissue ulceration or necrosis, but may also reveal an intraoral or extraoral fistula, mandibular discontinuity, or evidence of secondary local or systemic infection. It is of vital importance that the evaluating physician have a high index of suspicion that this presentation may be recurrent, or persistent, or even metastatic malignancy. Deep biopsy of the lesion is helpful with samples sent for pathology and bacteriology in guiding treatment of a secondary infection, if present. In the course of the evaluation of this patient, the treating radiation therapist should be consulted with a careful review of the pertinent radiation therapy records including the ports of radiation therapy, the total dose, dose per fraction, and timing of therapy. Any complications associated with the radiation treatment should be noted. A thorough dental examination is also performed in those patients with remaining dentition. If indicated, an experienced oral surgeon should be consulted. A history of preceding intraoral trauma should also be explored. Outside of the physical exam, radiographs will provide the most accurate estimate of the extent of the disease. The panorex provides a cost-effective useful assessment of the disease process, showing mottled areas of lucency with sclerotic areas at the edge of the involvement. In the progressed states, a pathological fracture or a sequestrum may also be identified. A CT scan (DentaScan) may provide useful information in detecting soft tissue in the area of bony resorption which may represent a tumor.

There are two primary goals in the treatment osteoradionecrosis of the mandible, elimination of the necrotic bone and improvement of the vascularity of the remaining radiation damaged tissues. With a change in the concept in the pathophysiology of osteoradionecrosis, the treatment of the disease has also undergone significant revision. An earlier protocol of treating this disease as advocated by Rankow and Weissman in the 1970’s, specifically describes a two stage conservative approach.

In the first stage, the patient was instructed to avoid alcohol, smoking, hot or cold foods, and all prosthodontic appliances in conjunction with a protracted course of systemic antibiotics (tetracycline), oral rinses, and analgesics.[42] At the end of one year of conservatively managing the problem, the patient with persistence of the disease was then placed in a second stage in which treatment was finally managed surgically with resection of necrotic bone. Hyperbaric oxygen therapy was not utilized. It is argued by several other authors that this lengthy, conservative approach ultimately lead to a large number of "non-responders" that fell in to the surgically managed category, often requiring a more extensive resection of bone than would have initially been performed. While Rankow and Weissman estimated that 25% of their patients were non-responders in using antibiotic / oral rinse / irritant avoidance therapy, a separate study by Daly and Crane, illustrated that a full 64% of their patients represented non-surgical failure when applying the identical approach.[43]

In a recent paper by Wong et. al, a retrospective chart review was performed to determine the effectiveness of non-surgical / nonhyperbaric oxygen conservative or simple management. Their definition of conservative management was local irrigation (saline solution or cholohexidine .2%), systemic antibiotics in acute infectious episodes, avoidance of irritants, and explicit oral hygiene instructions; whereas, simple management involved the above in addition to the gentle removal of identifiable sequestrum.[44] Again, the consistent use of hyperbaric oxygen therapy was not described in their findings. The results of the review showed that 69% of the patients had lesions which resolved, stabilized, or improved using a conservative or simple management plan, while avoiding surgical resection or hyperbarics.[45]

Of the two approaches, the sequestrectomy patients had a more favorable outcome with a reported 75% of the patients obtaining complete mucosal coverage with associated improving or stable lesions.[46] It was noted that sequestrum formation and removal was the most valuable predictor of clinical outcome. While sequestrum represents the bone’s natural defense response in which granulation tissue and subsequent scar tissue walls off the diseased tissue, it is the removal that facilitates secondary epitheliazation and healing.

Other institutions do not report such success in the treatment of osteoradionecrosis without resorting to more intensive surgical resection and / or the use of hyperbaric oxygen therapy. To most authors, antibiotics, oral rinses, and irritant avoidance is simply not clinically effective. Marx, et. al . states that the overall weakness inherent in non-surgical approaches is that significant amounts of necrotic tissue significantly impairs adequate wound healing.[47] It has been his clinical experience and several others that most wounds of osteoradionecrosis contain such a great quantity of necrotic bone that resorption is generally incomplete without ultimately resorting to surgical management. In response to the number of non-surgical failures, Marx proposed a treatment protocol, with hyperbaric oxygen therapy as an integral adjunct. The overall design of the Marx HBO / surgical protocol was to first revascularize the living, albeit radiation damaged, surrounding tissue and then, as usually indicated, surgical remove the non-living tissue. The criteria set forth for successful management included – freedom from pain, retention or reconstruction of mandibular continuity, restoration of mandibular function including the ability to prosthodontic appliances, if needed, and maintenance of intact mucosa over the bone.[48] The protocol follows through three stages. Those patients meeting the criteria for osteoradionecrosis enter stage I with the exception of those patients with a pathological fracture, orocutaneous fistula, or osteolysis approaching the inferior border of the mandible.

This subset of patients enter stage III automatically. Each stage I patient receives a total of 30 hyperbaric oxygen exposures at 2.4 atmospheres absolute pressure (ATA) for 90 minutes in a multiplace chamber or 2.0 ATA for 120 min in a monoplace chamber.[49] After completion, the wound is examined for improvement such as mucosal cover, resorption of non-viable bone, or a decrease in the size of the exposure. Those improving are labeled stage I responders and then complete additional dives up to 60 until it clinically assured that full mucosal covering is complete ; whereas, the stage I non-responders advance to stage II. During this stage, the patient undergoes a transoral debridement / sequestrectomy with attempts at primary mucosal closure.[50] If postoperative healing occurs, the patient undergoes an additional ten sessions of hyperbarics. In contrast, those patients showing evidence of wound dehiscence with bone exposure advance to stage III.

Those patients excluded from entering stage I because of fistula formation, fracture, or inferior border of the mandible osteolysis undergo initial hyperbaric oxygen therapy consisting of 30 dives. During stage III, the patients undergo mandibular resection of the necrotic segment until the bone margins yield viable bone, i.e. bleeding encountered.; furthermore, for an orocutaneous fistula, the involved skin is excised followed by closure.[51] The segments of the mandible are stabilized either with an external fixator or maxillomandibular fixation and the patient undergoes additional hyperbaric oxygen therapy post operatively. For reconstructive purposes, Marx advocates waiting ten weeks after resection stating this permits a graft to be placed into a sufficiently vascular and cellular bed with intact mucosa. Prior to reconstruction an additional 20 dives were planned with ten dives post operatively.[52]

Reconstruction of the mandible in these patients consisted of either autogenous particulate bone and marrow within a custom-made stainless steal metal crib or autogenous particulate bone and marrow within a freeze-dried allogenic bone framework. With adherence to this protocol, Marx noted resolution of all cases of osteoradionecrosis within one of the stages. More specifically, 15% resolved in stage I, 15% resolved during stage II, and the remainder (70%) resolved in stage III.[52] The merits of hyperbaric oxygen therapy has been exhaustively described in Marx, with the ultimate outcome of angiogenesis and cellular proliferation in an otherwise hypovascular-hypocellular-hypoxic tissue bed. Hyperbaric oxygen therapy, however, is generally insufficient provide adequate treatment for the disease, as evidenced by the fact that only 15% of the patients responding to stage I therapy, a non-surgical approach. Why these patients responded while 85% required surgical intervention reflects the individual response to radiation injury despite identical radiation treatment plans. These patients theoretically displayed less a degree of hypoxia, hypocellularity, and hypovascularity with a greater residual and peripheral cellular pool that can respond to hyperbaric oxygen. In a separate, more recent study by Wood, et. al, the Marx HBO/surgical protocol was followed showing that all patients similarly had a successful outcome. Their results support Marx’s earlier result that non-surgical approaches are rarely effective as a full 83% of this patient population required surgical intervention in conjunction with HBO for optimal treatment of this disease.[54]

The re-establishment of mandibular continuity after mandibular resection is challenging, especially when considering the proximity to oral contaminants, the compromised adjacent tissues, and the stress bearing requirements of a functional mandible. The options of reconstruction include non-vascularized corticocancellous particulate bone grafts or a vascularized flaps (pedicled or microvascular). Before the use of hyperbaric oxygen to prepare the recipient bed for a graft, the use of non-vascularized bone graft in irradiated beds showed a high failure rate, i.e. resorption and/or delayed infection, approaching 50%. [55] With the use of pre-reconstructive hyperbaric oxygen therapy under the Marx protocol, however, the success rate has improved to approximately 90%.[56] Proponents of non-vascularized bone grafts site the advantages, when compared to microvascular free tissue transfer, less donor site morbidity, technically less demanding, reduced operating time, and acceptable success rates when the recipient bed is prepared with hyperbaric oxygen treatments.[57] Disadvantages associated with non-vascularized corticocancellous bone grafts, however, are a high failure rate if oral cavity perforation occurs with resulting bacterial contamination, inability to perform during segmental resection requiring a second procedure, and the protracted healing time while creeping substitution occurs.[58]

For patients having a significant soft tissue or intraoral defect, a composite microvascular transfer is clearly the method of choice. The distinctive advantage to this reconstructive method is the ability to transfer a composite flap in which the oral lining is restored at the same time healthy vascularized bone is placed. In addition, this may be performed at the time of mandibular resection. Some of the disadvantages include the technical challenge, longer operative time, and reported greater donor site morbidity.[59] Regarding reconstructive efforts of the pedicled flaps, options include the trapezius osteomyocutaneous flap, the pectoralis osteomyocutaneous flap, and the sternocleidomastoid flap using a portion of the medial aspect of the clavicle.[60]

While the trapezius, sternocleidomastoid, and pectoralis muscles have been extensively used as myocutaneous flaps in the reconstruction of soft tissue defects in the head and neck, the use of these as osteomyocutaneous flaps for oromandibular reconstruction has been less than ideal. While the blood supply in free flaps is from direct perforator or nutrient vessels, in the pedicled flaps the blood supply is not as vigorous because the blood supply to the bony portion is through indirect perforators.[61] Because of this more tenuous blood supply, there are frequently noted non-union, late resorption, or occasional total necrosis of the bone. In addition, these flaps are limited in their arc of rotation and also in the amount of bone that may be transferred. Microvascular reconstruction has become more attractive and increasingly popular in optimally addressing the defect. Numerous osseous / osteocutaneous / osteomyocutaneous flaps have been described, including anterior rid, radial forearm, iliac crest, scapular, fibular, and more recently the clavipectoral osteomyocutaneous flap. When planning and carrying out microvascular procedures in heavily irradiated patients, arteriography is particularly helpful in assessing the status of the recipient vessels. Ideally, the particular microvascular flap used in the oromandibular reconstruction will bridge the defect with natural contour, provide a soft tissue portion that remains pliable and thin, contain enough density and bulk to provide for dental appliances or osseointegrated implants, and have the potential for sensory and motor innervation.[62]


FOOTNOTES

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Kuluth EV, Jain PR, Stutchell RN, Frich JC. A Study of Factors Contributing to the Development of Osteoradionecrosis of the Jaws. The Journal of Prosthetic Dentistry. 59 (2): 194 - 201. 1988.

Marx RE. Osteoradionecrosis: A New Concept of Its Pathophysiology. Journal of Oral and Maxillofacial Surgery. 41: 283 - 288. 1983.

Marx RE, Johnson RP. Studies in the Radiobiology of Osteoradionecrosis and Their Clinical Significance. Oral Surgery Oral Medicine Oral Pathology. 64 (4): 379 - 390. 1987.

Marx RE. A New Concept in the Treatment of Osteoradionecrosis. Journal of Oral and Maxillofacial Surgery. 41: 351 - 357. 1983.

Wood GA, Liggins SJ. Does Hyperbaric Oxygen Have a Role in the Management of Osteoradionecrosis. British Journal of Oral and Maxillofacial Surgery. 34: 424 - 427. 1996.

Wong JK, Wood RE, McLean M. Conservative Management of Osteoradionecrosis. Oral Surgery Oral Medicien Oral Pathology. 84: 16 - 21. 1997.

Curi MM, Dib LL. Osteoradionecrosis of the Jaws: A Retrospective Study of the Background Factors and Treatment in 104 Cases. Journal of Oral and Maxillofacial Surgery. 55: 540 -544. 1997.

Shaha AR, Corderio PG, Hidalgo DA, Spiro RH, Strong EW, Zlotolow I, Shah JP. Resection and Immediate Microvascular Reconstruction in the Management of Osteoradionecrosis of the Mandible. Head and Neck. 19: 406 - 411. 1997.

Marx RE, Ames JR. The Use of Hyperbaric Oxygen Therapy in bony Reconstruction in the Irradiated and Tissue Deficient Patient. Journal of Oral and Maxillofacial Surgery. 40: 412 - 420. 1982.

Ioannides C, Fossion E, Boeckx W, Hermans B, Jacobs D. Surgical Management of the Osteoradionecrotic Mandible With Vascularized Composite Flaps. Journal of Cranio - Maxillo - Facial Surgery 22: 330 - 334. 1994.

Hom DB, Adams GL, Monyak D. Irradiated Soft Tissue and Its Management. Otolaryngologic Clinics of North America. 28(5): 1003 - 1019. 1995.

Costantino PD, Friedman CD, Steinberg MJ. Irradiated Bone and Its Management. Otolaryngologic Clinics of North America. 28(5): 1021 - 1037. 1995.

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Clayman L. Management of Dental Extractions in Irradiated Jaws: A Protocol Without Hyperbaric Oxygen Therapy. Journal of Oral and Maxillofacial Surgery. 55: 275 - 281. 1997.

Marx RE Johnson JE, Kline SN. Prevention of Osteoradionecrosis: A Randomized Prospective Clinical Trial of Hyperbaric Oxygen Therapy Versus Penicillin. Journal of American Dental Association. 111: 49 - 54. 1985.

Epstein JB, Rea G, Wond GL, Spinelli J, Stevenson-Moore P. Osteoradionecrosis: Study of the Relationship of Dental Extractions in Patients Receiving Radiotherapy. Head and Neck Surgery. 10: 48 - 54. 1987.

Bras J, DeJonge HKT, VanMerkestyen JPR. Osteoradionecrosis of the Mandible: Pathogenesis. American Journal of Otolaryngology. 11: pgs 244 - 250. 1990.


1. Hom DB, Adams GL, Monyak D. Irradiated Soft Tissue and Its Management. Otolaryngologic Clinics of North America. 28(5): pgs 1006 - 1007. 1995.

2. Ibid, pg 1004 - 1005.

3. Ibid, pg 1006.

4. Ibid, pg 1004.

5. Bailey BJ. Head and Neck Surgery – Otolaryngology. J.B. Lippincott Company. pg 1043. 1993.

6. Hom DB, Adams GL, Monyak D. Irradiated Soft Tissue and Its Management. Otolaryngologic Clinics of North America. 28(5): pgs 1006 - 1007. 1995.

7. Ibid, pg 1024.

8. Ibid, pg 1025.

9. Ibid.

10. Marx RE. Osteoradionecrosis: A New Concept of Its Pathophysiology. Journal of Oral and Maxillofacial Surgery. 41: pg 283. 1983.

11. Meyer I. Infectious Diseases of the Jaws. Journal of Oral Surgery. 28: pg 17. 1970.

12. Marx RE. Osteoradionecrosis: A New Concept of Its Pathophysiology. Journal of Oral and Maxillofacial Surgery. 41: pg 283. 1983.

13. Ibid.

14. Ibid, pg 285.

15. Ibid, pg 288.

16. Sanger JR, Matloub HS, Yousif NJ, Larson DL. Management of Osteoradionecrosis of the Mandible. Clinics in Plastic Surgery. 20(3): pgs 518 - 519. 1993.

17. Costantino PD, Friedman CD, Steinberg MJ. Irradiated Bone and Its Management. Otolaryngologic Clinics of North America. 28(5): pg 1023. 1995.

18. Ibid.

19. Ibid.

20. Bras J, DeJonge HKT, VanMerkestyen JPR. Osteoradionecrosis of the Mandible: Pathogenesis. American Journal of Otolaryngology. 11: pgs 244 - 250. 1990.

21. Ibid.

22. Ibid.

23. Clayman L. Management of Dental Extractions in Irradiated Jaws: A Protocol Without Hyperbaric Oxygen Therapy. Journal of Oral and Maxillofacial Surgery. 55: pg 277. 1997.

24. Sanger JR, Matloub HS, Yousif NJ, Larson DL. Management of Osteoradionecrosis of the Mandible. Clinics in Plastic Surgery. 20(3): pg 520. 1993.

25. Kuluth EV, Jain PR, Stutchell RN, Frich JC. A Study of Factors Contributing to the Development of Osteoradionecrosis of the Jaws. The Journal of Prosthetic Dentistry. 59 (2): pg 200. 1988.

26. Sanger JR, Matloub HS, Yousif NJ, Larson DL. Management of Osteoradionecrosis of the Mandible. Clinics in Plastic Surgery. 20(3): pg 529. 1993.

27. Clayman L. Management of Dental Extractions in Irradiated Jaws: A Protocol Without Hyperbaric Oxygen Therapy. Journal of Oral and Maxillofacial Surgery. 55: pg 275. 1997.

28. Epstein JB, Rea G, Wond GL, Spinelli J, Stevenson-Moore P. Osteoradionecrosis: Study of the Relationship of Dental Extractions in Patients Receiving Radiotherapy. Head and Neck Surgery. 10: pg 52. 1987.

29. Curi MM, Dib LL. Osteoradionecrosis of the Jaws: A Retrospective Study of the Background Factors and Treatment in 104 Cases. Journal of Oral and Maxillofacial Surgery. 55: pg 543. 1997.

30. Marx RE, Johnson RP. Studies in the Radiobiology of Osteoradionecrosis and Their Clinical Significance. Oral Surgery Oral Medicine Oral Pathology. 64 (4): pg 384. 1987.

31. Ibid.

32. Marx RE Johnson JE, Kline SN. Prevention of Osteoradionecrosis: A Randomized Prospective Clinical Trial of Hyperbaric Oxygen Therapy Versus Penicillin. Journal of American Dental Association. 111: pg 50. 1985.

33. Ibid, pg 51.

34. Marx RE, Ames JR. The Use of Hyperbaric Oxygen Therapy in bony Reconstruction in the Irradiated and Tissue Deficient Patient. Journal of Oral and Maxillofacial Surgery. 40: pg 416. 1982.

35. Ibid.

36. Ibid.

37. Ibid

38. Marx RE Johnson JE, Kline SN. Prevention of Osteoradionecrosis: A Randomized Prospective Clinical Trial of Hyperbaric Oxygen Therapy Versus Penicillin. Journal of American Dental Association. 111: pg 53. 1985.

39. Marx RE, Johnson RP. Studies in the Radiobiology of Osteoradionecrosis and Their Clinical Significance. Oral Surgery Oral Medicine Oral Pathology. 64 (4): pg 387 - 389. 1987.

40. Ibid.

41. Ibid.

42. Marx RE. A New Concept in the Treatment of Osteoradionecrosis. Journal of Oral and Maxillofacial Surgery. 41: pg 351. 1983.

43. Ibid.

44. Wong JK, Wood RE, McLean M. Conservative Management of Osteoradionecrosis. Oral Surgery Oral Medicien Oral Pathology. 84: pg 17. 1997

45. Ibid, pg 20.

46. Ibid, pg 19.

47. Marx RE. A New Concept in the Treatment of Osteoradionecrosis. Journal of Oral and Maxillofacial Surgery. 41: pg 351. 1983.

48. Ibid, pg 355.

49. Ibid.

50. Ibid, pg 353

51. Ibid.

52. Ibid, pg 354.

53. Ibid, pg 355.

54. Wood GA, Liggins SJ. Does Hyperbaric Oxygen Have a Role in the Management of Osteoradionecrosis. British Journal of Oral and Maxillofacial Surgery. 34: pgs 424 - 25. 1996

55. Sanger JR, Matloub HS, Yousif NJ, Larson DL. Management of Osteoradionecrosis of the Mandible. Clinics in Plastic Surgery. 20(3): pg 524. 1993.

56. Costantino PD, Friedman CD, Steinberg MJ. Irradiated Bone and Its Management. Otolaryngologic Clinics of North America. 28(5): pg 1033. 1995.

57. Ibid, pg1034.

58. Sanger JR, Matloub HS, Yousif NJ, Larson DL. Management of Osteoradionecrosis of the Mandible. Clinics in Plastic Surgery. 20(3): pg 525. 1993.

59. Costantino PD, Friedman CD, Steinberg MJ. Irradiated Bone and Its Management. Otolaryngologic Clinics of North America. 28(5): pg 1035. 1995

60. Sanger JR, Matloub HS, Yousif NJ, Larson DL. Management of Osteoradionecrosis of the Mandible. Clinics in Plastic Surgery. 20(3): pg 525. 1993.

61. Ibid.

62. Seikaly H, Calhoun K, Rassekh CH, and Slaughter D. The Clavipectoral Osteomyocutaneous Free Flap. Otolaryngology - Head and Neck Surgery. 117 (5): pg 547. 1997.