Radiation Therapy and Mandibular Osteoradionecrosis: State of the Art.

PURPOSE OF REVIEW: This article aims to provide an update on literature data related to mandibular osteoradionecrosis (MORN) secondary to the irradiation of the head and neck region. RECENT FINDINGS: Radiotherapy (RT) plays a crucial role in the contemporary management of head and neck cancer (HNC) patients and, despite intensity-modulated technique (IMRT), mandibular osteoradionecrosis (MORN) remains a significant RT-related complication. Based on its clinical manifestation, MORN can negatively affect patients' quality of life. Preventive interventions should be prioritized. This manuscript is expected to represent an opportunity to guide a clear proposal for clinical measures in the individual MORN situations.

Oral Cavity Reconstruction Outcomes Using a Porcine Urinary Bladder Matrix: A Retrospective Case Series.

OBJECTIVE: The purpose of this study is to assess healing outcomes in full-thickness mucosal wounds following the use of a porcine urinary bladder matrix to augment mixed oral cavity repairs. MATERIALS AND METHODS: A retrospective chart analysis was conducted over a 58-month timespan. Participants included individuals with osteoradionecrosis. Descriptive measures obtained in the postoperative setting were used to examine wound healing outcomes. RESULTS: Thirty-nine encounters with 35 patients met inclusion criteria for assessment. The mean defect size repaired was 14 cm2. Successful healing occurred in 64% of cases. Scarring was observed in 10 cases, and 3 cases demonstrated transient functional deficits. Reapplication of the xenograft was required in 4 cases. Only 1 acute event of hemorrhage and 1 infection were observed in the postoperative period. CONCLUSIONS: Use of porcine urinary bladder matrix grafts for oral cavity reconstruction was well tolerated in a diverse number of wound scenarios with a relatively low risk of postoperative complication. The use of porcine urinary bladder matrix was not observed to provide any noteworthy advantages for the healing of recalcitrant osteoradionecrosis wounds.

Hyperbaric Oxygen Therapy as an Adjunct for Treating an Individual with Poorly Healing Bilateral Mandibular Fractures Suspect of Developing Towards Osteomyelitis: A Case Report and Clinical Experience.

PURPOSE: To present a case that benefited from utilizing hyperbaric oxygen therapy in conjunction with antibiotics for a non-healing mandibular fracture that was highly suspicious of osteomyelitis. Also, to discuss research set forth by Undersea and Hyperbaric Medical Society that supports the use hyperbaric oxygen in such cases. CASE: A 25-year-old male status post fist to face resulting in bilateral mandibular fracture. He underwent two surgeries in an attempt to plate the fracture with the assistance of a bone graft. After failure of the bone graft and significant soft tissue wound breakdown, the surgeon was concerned for osteomyelitis and began therapy with intravenous antibiotics and hyperbaric oxygen therapy. CONCLUSION: The patient completed 30 hyperbaric oxygen treatments and 30 d of intravenous antibiotics. Clinically, the patient responded well and showed healed intraoral wounds and an objective decrease in erythrocyte sedimentation rate over the course of treatment. Unfortunately, on serial imaging the patient showed to have fibrous non-bony union of left fracture site. Even though the patient will need a final definitive plate for his fracture, it will be performed from an extraoral approach with no evidence of underlying infection.

Quality of Life after Free Fibula Flap Reconstruction of Segmental Mandibular Defects.

BACKGROUND: Free fibula flap (FFF) is considered gold standard in the reconstruction of mandibular defects. Despite the frequent use, patients' quality of life (QoL) after reconstruction has been sparsely investigated. This study aims to evaluate QoL and outcomes in patients who have undergone FFF reconstruction of segmental mandibular defects. METHODS: A retrospective cohort study of consecutive patients (n = 73) operated at a single center during the years 2000 to 2014 was performed. Charts were reviewed and all living patients (n = 41) were invited to fill out three quality of life questionnaires (QLQ): SF-36, EORTC QLQ-C30, and QLQ-H&N35. Factors associated with poor outcome were derived from regression models and the results of the QLQs were compared with Swedish reference populations. Subgroup analysis was performed for two groups depending on reconstructive indication: cancer and osteoradionecrosis (ORN). RESULTS: The response rate of the QLQs was 93%. General QoL did not differ from reference populations, but the study group had significantly larger proportions of poor functioning patients in three domains in EORTC QLQ-C30: global health status, role functioning, and social functioning. Patients also reported a high incidence of poor functioning/high symptom burden in EORTC QLQ-H&N35, with a significantly higher frequency in the ORN group compared with the cancer group for the domains "swallowing" and "social eating." The overall flap success rate was 92% and complication rate was 48%. Previous surgery had a significant association with reoperation due to bleeding, and longer duration of surgery was significantly associated with local infection. CONCLUSION: When evaluated with validated QLQs, most patients experienced persistent functional loss in one or several domains, but still perceived a general QoL that is close to that of reference populations. Patients having ORN as the indication for surgery, as compared with cancer, reported a higher frequency of poor functioning patients in disease-specific QoL domains.

Predictive factors for osteoradionecrosis of the jaws: A retrospective study.

BACKGROUND: Osteoradionecrosis of the jaw (ORNJ) is a well-recognized complication of radiotherapy. The purpose of this study was to assess predictive factors for the development of ORNJ. METHODS: A retrospective study of 325 patients with head and neck squamous cell carcinoma (HNSCC) treated at one institution between January 1, 1999, and December 31, 2008, was conducted. Outcome measure was the presence/absence of ORNJ. Time to event was recorded and Cox proportional hazard regression analysis was used to determine statistically significant predictive factors. RESULTS: Fifty-nine patients had ORNJ. Statistical analysis using Cox regression analysis identified several statistically significant variables: dentoalveolar surgery; peri-resective surgery of the jaw; continued tobacco usage after radiotherapy, diabetes mellitus type 2 (DM2); and total radiation dose. CONCLUSION: Patients at greater risk of developing ORNJ can be identified and measures can be instituted to reduce its incidence and expedite management when it does occur.

Osteoradionecrosis: a review of pathophysiology, prevention and pharmacologic management using pentoxifylline, α-tocopherol, and clodronate.

A significant complication of radiotherapy to the head and neck for cancer treatment is osteoradionecrosis (ORN) of the jaws. The management of ORN can be complex and often requires a multimodality approach. Nonsurgical treatments with or without adjunct measures and surgical interventions have all been employed on the basis of staging of the disease process. New theories on the pathophysiology of ORN have led to the identification of novel treatment modalities, including pharmacologic management using pentoxifylline, tocopherol, and clodronate (together referred to as "Pentoclo"). In this review article, we discuss the definition and staging of ORN, its etiology and pathophysiology, and traditional treatment options and present the available information on pentoxifylline, tocopherol, and clodronate and their use in combined therapy for ORN. Limited studies to date have demonstrated the effective pharmacologic use of Pentoclo in treating ORN and radiation-induced injury at other body sites. Further research is necessary to elucidate any potential role for the use of Pentoclo in the management of this debilitating disease process.

Axial four-dimensional computed tomographic images to analyze crosswise differences in protrusive condylar movement in patients who underwent mandibulectomy and free flap reconstruction.

OBJECTIVE: Few studies evaluate condylar movement following mandibular reconstruction. The main objective of this study was to show that axial four-dimensional computed tomography (4DCT) could visualize bilateral protrusive condylar movement directly. We used axial 4DCT images to assess condylar protrusion in patients who underwent mandibular reconstruction. METHODS: We enrolled seven healthy volunteers (median age 30 years, range 27-38 years) and seven patients (median age 65 years, range 52-80 years), who underwent mandibulectomy (segmental in five, hemi in one, marginal in one) and free flap reconstruction (using the fibula in six and the radial forearm in one). Six study subjects were instructed to masticate a cookie during the 4DCT scan (the seventh made chewing motions). The distance between the most anterior and posterior positions of the bilateral condyles on 4DCT (axial view) images was then measured and compared between controls and patients using the Mann-Whitney U-test. RESULTS: The crosswise difference in the distances of condylar protrusion was significantly greater in patients than in the controls. CONCLUSION: Axial 4DCT images can visualize a bilateral condylar protrusive path. Axial 4DCT images for patients who have undergone mandibulectomy and reconstruction may be useful for evaluation of functional movement of condyles.

Symptom burden and dysphagia associated with osteoradionecrosis in long-term oropharynx cancer survivors: A cohort analysis.

OBJECTIVE: The purpose is to examine the relationship between mandibular osteoradionecrosis (ORN) and chronic dysphagia in long-term oropharynx cancer (OPC) survivors, and to determine the perceived symptom burden associated with ORN. MATERIALS AND METHODS: Medical records of 349 OPC patients treated with bilateral IMRT and systemic therapy were reviewed. ORN was graded using a published 4-point classification schema. Patients were considered to have chronic dysphagia if they had aspiration pneumonia, stricture or aspiration detected by fluoroscopy or endoscopy, and/or feeding tube dependence in long-term follow-up ⩾1year following radiotherapy. MD Anderson Symptom Inventory - Head and Neck Module (MDASI-HN) scores were analyzed in a nested cross-sectional survey sample of 118 patients. RESULTS: 34 (9.7%, 95% CI: 6.8-13.3%) patients developed ORN and 45 (12.9%, 95% CI: 9.6-16.9%) patients developed chronic dysphagia. Prevalence of chronic dysphagia was significantly higher in ORN cases (12/34, 35%) compared to those who did not develop ORN (33/315, 11%, p<0.001). ORN grade was also significantly associated with prevalence of dysphagia (p<0.001); the majority of patients with grade 4 ORN requiring major surgery (6 patients, 75%) were found to have chronic dysphagia. Summary MDASI-HN symptom scores did not significantly differ by ORN grade. Significantly higher symptom burden was reported, however, among ORN cases compared to those without ORN for MDASI-HN swallowing (p=0.033), problems with teeth and/or gums (p=0.016) and change in activity (p=0.015) item scores. CONCLUSIONS: ORN is associated with excess burden of chronic dysphagia and higher symptom severity related to swallowing, dentition and activity limitations.

The histological and histomorphometric changes in the mandible after radiotherapy: An animal model.

PURPOSE: Approximately 5% of irradiated head and neck cancer patients develop osteoradionecrosis of the mandible. The current non-surgical treatment options for osteoradionecrosis have limited effects and are based on a small number of studies. Therefore, we aimed to enhance the understanding of the pathophysiology of osteoradionecrosis by investigating changes induced by external irradiation in mini-pigs. METHODS: Sixteen Göttingen mini-pigs were divided into four groups for the application in two fractions with total equivalent radiation dosages of 25, 50, 70 Gray, and one group served as control. Thirteen weeks after irradiation, the left lateral teeth the mandible were removed and implants were placed. The pigs were sacrificed twenty-six weeks after irradiation, and the bone samples were stained with Masson's trichrome. RESULTS: The amount of fibrosis, resorption lacunae, necrosis, and the woven/lamellar bone ratios were increased after higher radiation dosages. The diameter of the lumen of the inferior alveolar artery was reduced depending on the irradiation dosages. The rate of bone remodeling decreased after irradiation. CONCLUSION: Both surgery and increasing irradiation dosages cause architectural bone changes and damage the vascularization. This might result in a chronic hypoxic state of the mandibular bone. In general, the bone formation rate was markedly decreased after radiotherapy.

Ameliorative effect of black grape juice on systemic alterations and mandibular osteoradionecrosis induced by whole brain irradiation in rats.

PURPOSE: Whole brain irradiation (WBI) causes a variety of secondary side-effects including anorexia and bone necrosis. We evaluated the radiomodifying effect of black grape juice (BGJ) on WBI alterations in rats measuring food and water intake, body weight, hemogram, and morphological and histological mandibular parameters. MATERIALS AND METHODS: Forty male rats (200-250 g) were exposed to eight sessions of cranial X-ray irradiation. The total dose absorbed was 32 Gy delivered over 2 weeks. Four groups were defined: (i) NG: non-irradiated, glucose and fructose solution-supplemented (GFS); (ii) NJ: non-irradiated, BGJ-supplemented; (iii) RG: irradiated, GFS-supplemented; and (iv) RJ: irradiated, BGJ-supplemented. Rats received daily BGJ or GFS dosing by gavage starting 4 days before, continuing during, and ending 4 days after WBI. RESULTS: RJ rats ingested more food and water and showed less body weight loss than RG rats during the irradiation period. Forty days after WBI, irradiated animals started losing weight again compared with controls as a consequence of masticatory hypofunction by mandibular osteoradionecrosis (ORN). Osteoclastic activity and inflammation were apparent in RG rat mandibles. BGJ was able to attenuate the severity of ORN as well as to improve white and red blood cell counts. CONCLUSIONS: Fractionated whole brain irradiation induces mandibular changes that interfere with normal feeding. BGJ can be used to mitigate systemic side-effects of brain irradiation and ORN.

New perspectives on the conservative management of osteoradionecrosis of the mandible: A literature review.

Over the last decades, several therapeutic options were considered in the treatment of the osteoradionecrosis (ORN) of the mandible, including supportive measures, ultrasound therapy, corticosteroids, hyperbaric oxygen, surgical resection with reconstruction, and, more recently, drugs capable of reversing the fibroatrophic process. Once established, the ORN does not spontaneously disappear and a standard treatment has not yet been defined. The clear clinical effectiveness of hyperbaric oxygen therapy (HBOT) varies according to the literature and there are some economic/logistic issues to be considered; the triplet tocopherol/pentoxifylline/clodronate demands greater evidence from randomized clinical trials and also resilience from the patient, given the long treatment duration and its possible side effects. Controversy around the ideal treatment of the initial stage ORN of the mandible persists. More rigorous randomized prospective trials are essential. The purpose of this article was to review the relevant literature on the physiopathology of ORN of the mandible and discuss the new perspectives of its conservative treatment. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1708-1716, 2016.

Neurologic late effects associated with radiologic evidence of vertebral osteoradionecrosis after salvage laryngectomy: A syndrome associated with survivors of laryngeal and hypopharyngeal cancer.

BACKGROUND: Delayed nonspecific posterior neck pain after pharyngeal instrumentation can be associated with a syndrome of rapidly progressive neurologic embarrassment. We present this cohort to help define the syndrome and aid in early detection. METHODS: We conducted a retrospective case series of 6 patients presenting from 2003 to 2012 with a history of laryngeal or hypopharyngeal squamous cell carcinoma (SCC) who underwent radiotherapy (RT) or chemoradiotherapy (CRT) followed by salvage laryngectomy. RESULTS: Posterior neck and upper back pain developed a mean of 27.5 days after instrumentation of the pharynx (reconstruction after laryngectomy or pharyngeal dilation). Myelopathy developed an average of 21.5 days after the onset of posterior neck pain. Five patients required urgent decompression. Three patients developed quadriplegia. The disease-specific mortality was 50%. CONCLUSION: There is a syndrome of late neurological effects after RT, salvage surgery, and pharyngeal instrumentation that is associated with high morbidity and mortality. © 2016 Wiley Periodicals, Inc. Head Neck 38:1187-1193, 2016.

Development of mandibular osteoradionecrosis in rats: Importance of dental extraction.

OBJECTIVES: To develop an animal model of mandibular osteoradionecrosis (ORN) using a high-energy radiation source (as used in human therapeutics) and to assess the role of tooth extraction on ORN development. MATERIALS AND METHODS (STUDY DESIGN): Ten animals were irradiated with a single 35- or 50-Gy dose. Three weeks later, the second left mandibular molar was extracted from three animals in each group. Nine weeks after irradiation, the animals were euthanized, with an injection of contrast agent in the bloodstream to highlight vascularization. Mandibles were harvested and studied using micro-CT, histology, tartrate-resistant acid phosphatase activity and scanning electron microscopy. RESULTS: This study demonstrates that a single 50-Gy dose associated with molar extraction is necessary for ORN development. In these conditions, absence of healing of the mucosa and bone, dental effects, fibrosis, an increase in osteoclast activity and a decrease in vascularization were observed. We also determined that molar extraction increases the impact of the cellular effects of radiation. CONCLUSION: The mandibular ORN animal model was validated after 50-Gy irradiation and molar extraction. The results of this study therefore support an animal ORN model and tissue engineering strategies will now be developed to regenerate bone for patients with head and neck cancer.

Postirradiated carotid blowout syndrome in patients with nasopharyngeal carcinoma: a case-control study.

BACKGROUND: Carotid blowout syndrome is one of the most devastating complications of nasopharyngeal carcinoma (NPC) therapy. METHODS: A retrospective review was conducted from January 2004 to April 2013. Thirty-one patients with carotid blowout syndrome were enrolled and a case control study was conducted to analyze the risk factors. RESULTS: When a comparison was made between the carotid blowout syndrome and matched non-bleeding group, there was a significantly higher local recurrence rate and prevalence of skull base osteoradionecrosis (ORN) in the carotid blowout syndrome group compared to those of the control group (both p < .001). The hazard ratio of carotid blowout syndrome was 3.599 between patients with or without reirradiation (95% confidence interval, 1.465-8.839; p = .005, adjusted for nasopharyngectomy and chemotherapy) using a Cox proportional hazard model. CONCLUSION: Reirradiation and skull base ORN are strong predisposing factors for carotid blowout syndrome, and therefore they should be mentioned in the informed consent form before treatment.

Radionecrosis of the frontal lobe as a consequence of malignant ethmoid tumor management: incidence, diagnosis, risk factors, prevention and management.

Malignant ethmoid tumors are treated by surgery followed by radiotherapy. This study aimed to evaluate the incidence, risk factors and outcome of radionecrosis of frontal lobe and determine preventive measures. Retrospective study of ethmoid malignancies treated from 2000 to 2011. All patients underwent surgery with/without anterior skull base resection using endoscopic or external approaches followed by irradiation (mean dose 64 Gy). Median follow-up was 50 months. Eight of 50 patients (16 %) presented with fronto-basal radionecrosis, connected to duraplasty, with a latent interval of 18.5 months. Although asymptomatic in six, radionecrosis triggered seizures and required surgery in two cases. Survival was not impacted. Risk factors included dyslipidemia, occurrence of epilepsy and dural resection. Radionecrosis may result from the combination of anterior skull base resection and radiotherapy for the treatment of ethmoid malignancies. Preventive measures rely on improving the duraplasty and optimization of the Gy-dose delivery.

Parathyroid hormone therapy mollifies radiation-induced biomechanical degradation in murine distraction osteogenesis.

OBJECTIVE: Descriptions of mandibular distraction osteogenesis for tissue replacement after oncologic resection or for defects caused by osteoradionecrosis have been limited. Previous work demonstrated radiation decreases union formation, cellularity and mineral density in mandibular distraction osteogenesis. The authors posit that intermittent systemic administration of parathyroid hormone will serve as a stimulant to cellular function, reversing radiation-induced damage and enhancing bone regeneration. METHODS: Twenty male Lewis rats were randomly assigned to three groups: group 1 (radiation and distraction osteogenesis, n = 7) and group 2 (radiation, distraction osteogenesis, and parathyroid hormone, n = 5) received a human-equivalent dose of 35 Gy of radiation (human bioequivalent, 70 Gy) fractionated over 5 days. All groups, including group 3 (distraction osteogenesis, n = 8), underwent a left unilateral mandibular osteotomy with bilateral external fixator placement. Distraction osteogenesis was performed at a rate of 0.3 mm every 12 hours to reach a gap of 5.1 mm. Group 2 was injected with parathyroid hormone (60 µg/kg) subcutaneously daily for 3 weeks after the start of distraction osteogenesis. On postoperative day 40, all left hemimandibles were harvested. Biomechanical response parameters were generated. Statistical significance was considered at p ≤ 0.05. RESULTS: Parathyroid hormone-treated mandibles had significantly higher failure load and higher yield than did untreated mandibles. However, these values were still significantly lower than those of nonirradiated mandibles. CONCLUSIONS: The authors have successfully demonstrated the therapeutic efficacy of parathyroid hormone to stimulate and enhance bone regeneration in their irradiated murine mandibular model of distraction osteogenesis. Anabolic regimens of parathyroid hormone, a U.S. Food and Drug Administration-approved drug on formulary, significantly improve outcomes in a model of postoncologic craniofacial reconstruction.

The effect of bisphosphonate therapy on neutrophil function: a potential biomarker.

Bisphosphonate-related osteonecrosis of the jaws (BRONJ) occurs subsequent to intravenous and oral bisphosphonate exposure in a small subset of patients. The identification of the pathophysiologic mechanisms has not been fully elucidated. Evidence of concurrent bacterial colonization at sites of bone necrosis, previous reports of neutrophil-related complications in some patients taking some bisphosphonates, along with perturbed neutrophil function in bisphosphonate-treated mice, suggest an innate immune role in the development of BRONJ. This study investigated neutrophil function in BRONJ patients to determine if neutrophil functional defects may serve as a potential biomarker for BRONJ susceptibility. Two populations were studied: patients with BRONJ and those beginning intravenous pamidronate. Healthy control patients were used for comparison. Twenty-three patients with BRONJ and five patients who were beginning pamidronate therapy provided neutrophil samples from the mouth (oral rinses) and from blood. Neutrophils from the population of patients with BRONJ and from those post-pamidronate treatment showed lower reactive-oxygen species production and impaired chemotaxis relative to controls. These data suggest that a compromise in neutrophil function may be a potential biomarker for BRONJ susceptibility.

Low-intensity ultrasound accelerates mandibular implant bone integration in dogs with mandibular osteoradionecrosis.

BACKGROUND: To investigate whether low-intensity ultrasound accelerates healing in bone tissues close to dental implants with osteoradionecrosis (ORN) of the mandible and is suitable for development as a therapy in patients with dental implants receiving radiotherapy. MATERIALS AND METHODS: Dog models of radiative bone injury surrounding dental implants in both sides of mandible were established by four treatment methods of radiotherapy, each 15Gy. After radiative treatment, antibiotics were administered and the left injury was treated with ultrasound and the right with debridement. Measures for evaluation included spiral computed tomography (SCT), Micro-CT, microvessel density, and pull-out experiment, and data were collected and analyzed. RESULTS: After 4months of radiotherapy, both sides of mandible displayed preclinic symptom of radiative osteonecrosis. Microvessel density of the side treated by ultrasound was 6.2152±0.6508 and that of the debridement side was 3.8490±0.8954 (P<0.05). Micro-CT results showed that bone volume fraction of trabecula, thickness of trabecula, trabecula spacing, ratio of bone surface area to bone volume, and trabecula number of the ultrasound-treated mandible were 0.3605±0.0337, 0.0287±0.0045, 0.0369±0.0073, 71.6124±14.1649, and 7.2915±1.4937, whereas those of the debridement side were 0.1779±0.0178, 0.0151±0.0021, 0.6623±0.1125, 33.2686±5.949, and 5.0689±0.5028, respectively; statistical significance was observed (P<0.05). Pull-out experiment suggested that pull-out strength of the ultrasound-treated side was 0.5793±0.1066 whereas that of the debridement side was 0.2980±0.0243, representing a statistical significance (P<0.05). CONCLUSIONS: Low-intensity ultrasound can accelerate the healing of bone tissues surrounding dental implants in osteoradionecrosis of the mandible animals.