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.