Mesenchymal stem cell therapy for treatment of osteoradionecrosis of mandible in head and neck surgery patients - A way forward into the future with promising clinical Outcomes.

Managing osteoradionecrosis is an integral part of complication management in head and neck cancer patients. While essentially an infection, the management of this complication has a considerable task for head and neck surgeons. While various measures have been discussed for the management, stem cells injection therapy is a potential management option. Mesenchymal stem cell therapy provides the local tissue with growth factors and proliferative cells that can aid a radiated tissue in the healing process. The article intends to review the bedrock of the pathology, ranging from pathophysiological and the epidemiological concerns to sparking a potential discussion on the use of mesenchymal stem cell therapy in osteoradionecrosis of mandible in head and neck cancer surgery and thus the ensuing future of the regenerative medicine. Moreover, the article has considered the management option in a developing nation thus explaining the procedural as well as the financial pitfalls and has highlighted the potential loop holes to be addressed in the management of osteoradionecrosis with stem cell therapy.

Hyperbaric oxygen treatment of mandibular osteoradionecrosis: Combined data from the two randomized clinical trials DAHANCA-21 and NWHHT2009-1.

PURPOSE: Osteoradionecrosis (ORN) of the mandible is a serious complication of head and neck radiotherapy. This study aims to investigate the effect of hyperbaric oxygen (HBO) treatment on ORN in two randomized, controlled multicentre trials. METHODS AND MATERIALS: Patients with ORN with indication for surgical treatment were randomised to either group 1: surgical removal of necrotic mandibular bone supplemented by 30 pre- and 10 postoperative HBO exposures at 243 kPa for 90 min each, or group 2: surgical removal of necrotic bone only. Primary outcome was healing of ORN one year after surgery evaluated by a clinically adjusted version of the Common Toxicity Criteria of Adverse Events (CTCAE) v 3.0. Secondary outcomes included xerostomia, unstimulated and stimulated whole salivation rates, trismus, dysphagia, pain, Activities of Daily Living (ADL) and quality of life according to EORTC. Data were combined from two separate trials. Ninety-seven were enrolled and 65 were eligible for the intent-to-treat analysis. The 33% drop-out was equally distributed between groups. RESULTS: In group 1, 70% (21/30) healed compared to 51% (18/35) in group 2. HBO was associated with an increased chance of healing independent of baseline ORN grade or smoking status as well as improved xerostomia, unstimulated whole salivary flow rate, and dysphagia. Due to insufficient recruitment, none of the endpoints reached a statistically significant difference between groups. ADL data could only be obtained from 50 patients. CONCLUSION: Hyperbaric oxygen did not significantly improve the healing outcome of osteoradionecrosis after surgical removal of necrotic bone as compared to standard care (70% vs. 51%). This effect is not statistically significant due to the fact that the study was underpowered and is therefore prone to type II error.

[Predictive factors for mandibular osteoradionecrosis after irradiation of head and neck cancers]. / Facteurs prédictifs de l'ostéoradionécrose mandibulaire après irradiation des cancers des voies aérodigestives supérieures.

The identification of the different risk factors for mandibular osteoradionecrosis (ORN) must be done before and after the management of patients with head and neck cancer. Various clinical criteria for this severe radiation-induced complication are related to the patient (intrinsic radiosensitivity, malnutrition associated with thin weight loss, active smoking intoxication, microcapillary involvement, precarious oral status, hyposalivation) and/or related to the disease (oral cavity, large tumor size, tumor mandibular invasion). Therapeutic risk factors are also associated with a higher risk of ORN (primary tumor surgery, concomitant radio-chemotherapy, post-irradiation dental avulsion, preventive non-observance with the absence of stomatological follow-up and daily installation of gutters fluoride and, non-observance curative healing treatments). Finally, various dosimetric studies have specified the parameters in order to target the dose values distributed in the mandible, which increases the risk of ORN. An mean mandibular dose greater than 48-54Gy and high percentages of mandibular volume receiving 40 to 60Gy appear to be discriminating in the risk of developing an ORN.

Radiation therapy in head and neck cancer.

This review summarizes the beginning of radiotherapy, techniques of modern radiation therapy with different types, toxicities induced by radiotherapy and their management. Head and neck radiation therapy is still improving for the better management and control of the cancer and induced radiotherapy toxicities.

Is Adjunctive Hyperbaric Oxygen Treatment Alone or with Surgery the Proper Management for Active and Persistent Osteoradionecrosis?

ABSTRACT: This study enrolled patients with stage 3 osteoradionecrosis. There were three treatment modalities: antibiotics, hyperbaric oxygen therapy (HBOT), and surgery. Complete healing was the primary outcome. Multiple logistic regression analysis demonstrated that surgery with HBOT improved wound healing better than HBOT alone.

Successful application of antimicrobial photodynamic and photobiomodulation therapies for controlling osteoradionecrosis and xerostomia after laryngeal carcinoma treatment: A case report of full oral rehabilitation.

We present a clinical case where a conservative treatment based on photonics [antimicrobial Photodynamic Therapy (aPDT) associated to Photobiomodulation therapy (PBMT)] of a patient with osteoradionecrosis (ORN) due to radiotherapy treatment of a laryngeal cancer. As a result of this combined treatment the ORN was controlled (e.g. the necrosis, infection and suppuration disappeared). Moreover, the symptoms reported by the patient (pain and xerostomia) also diminished along with the repair of oral mucosa. In future cases this combined therapy (e.g. PBM therapy and the aPDT) will be further examined.

Lumbar vertebral osteoradionecrosis: a rare case report with 10-year follow-up and brief literature review.

BACKGROUND: Osteoradionecrosis (ORN) is a complication that occurs after radiotherapy for head or neck malignancies. ORN of the spine is rare, with only few cases affecting the cervical spine reported to date. To our knowledge, no case of lumbar ORN has been reported. We report a rare case of ORN in the lumbar spine that occurred 2 years after radiotherapy and perform a literature review. CASE PRESENTATION: We present a case of lumbar ORN that occurred 2 years after radiotherapy for gallbladder carcinoma. The patient was successfully treated conservatively and followed up for > 10 years. CONCLUSIONS: ORN of the spine is a rare complication of radiotherapy. Spinal ORN is clinically described as a chronic disease with a slow onset. The most common presenting symptom of spinal ORN is pain. However, as ORN progresses, spinal kyphosis and instability can lead to neurological compression and thus to induced myelopathy or radiculopathy. Treatment of spinal ORN is comprehensive, including orthosis, medication, hyperbaric oxygen therapy, surgery, and new treatment combinations of pentoxifylline and tocopherol. The surgical rate for spinal ORN is relatively high.

Teriparatide therapy for severe, refractory osteoradionecrosis of the jaw.

Although osteoradionecrosis (ORN) is a serious complication of craniofacial radiotherapy, the current management methods remain suboptimal. Teriparatide (TPTD), a recombinant human parathyroid hormone (1-34), has shown beneficial effects on osseous regeneration in medication-related osteonecrosis of the jaw or periodontitis. However, TPTD therapy in irradiated bones has not been indicated yet because of the theoretical risk of osteosarcoma seen in rat models. Hence, we first report here two patients with tongue cancer with late-emerging ORN who were successfully treated with TPTD for 4-6 months with serum calcium and vitamin D supplementation. In contrast to the usual progress of ORN, the bone defect regenerated well and bone turnover markers including serum C-terminal telopeptide of type 1 collagen and osteocalcin were restored with TPTD therapy. Our experience might suggest that TPTD therapy with careful monitoring can provide an effective treatment option for patients with ORN in select refractory cases, with the benefits outweighing the potential risks.

Surgical management of temporal bone osteoradionecrosis: Single surgeon experience of 47 cases.

PURPOSE: To report the outcomes of 47 patients with temporal bone osteoradionecrosis treated primarily with surgical resection in order to analyze whether flap type and hyperbaric oxygen use affect wound breakdown. MATERIALS AND METHODS: Between January 1998 and January 2016, 47 patients were treated for temporal bone osteoradionecrosis with surgery. Some patients were also treated with hyperbaric oxygen. Resection of grossly necrotic temporal bone was followed by immediate reconstruction with local, regional, or free flaps. Minimum follow-up was 6months. If patients had breakdown of their initial reconstructions, secondary reconstruction was performed with either a regional or free flap. During the post-operative period, wound breakdown, flap complications, and patient survival were noted. RESULTS: 30 patients developed ORN from primary radiotherapy while 17 had post-operative radiation. It was found that wound breakdown was significantly associated with type of flap reconstruction (p=0.02) with local flap reconstruction portending a poorer prognosis. Hyperbaric oxygen was not associated with decreased wound breakdown (p=0.5). CONCLUSIONS: Surgical treatment can be an effective treatment for temporal bone osteoradionecrosis, without hyperbaric oxygen providing any additional benefit. Reconstruction with regional or free flaps may be a more reliable method to resurface defects compared to local flaps.

The Use of Hyperbaric Oxygen for the Prevention and Management of Osteoradionecrosis of the Jaw: A Dana-Farber/Brigham and Women's Cancer Center Multidisciplinary Guideline.

BACKGROUND: Osteoradionecrosis of the jaw (ORN) is an infrequent yet potentially devastating complication of radiation therapy to the head and neck region. Treatment options include antimicrobial therapy, local sequestrectomy, resection, and the use of hyperbaric oxygen (HBO). Published data on ORN are difficult to compare because of the lack of a universally accepted classification and staging system, and the literature on the use of HBO to either prevent or successfully manage ORN is controversial and inconclusive. Therefore, we aimed to establish a standard approach for using HBO at our institution. MATERIALS AND METHODS: A literature search was conducted of articles published in the English language between January 1980 and January 2016. Retrieved articles were evaluated by two independent reviewers. Isolated case reports, abstracts, case series, review articles, and cohort studies without a control group were excluded; summary data were extracted from the remaining studies. A panel of experts from Head and Neck Oncology and Oral Medicine from the Dana-Farber Cancer Institute and Brigham and Women's Hospital reviewed the summary data and established multidisciplinary guidelines on the use of HBO for the prevention and management of ORN. RESULTS: Seven studies were evaluated and reviewed by the multidisciplinary panel. There was no consistent evidence in support of HBO for either the prevention or management of ORN. CONCLUSION: Based on the available evidence and expert opinion, routine use of HBO for the prevention or management of ORN is not recommended and is rarely used at our institution. The Oncologist 2017;22:343-350 IMPLICATIONS FOR PRACTICE: The Division of Head and Neck Oncology of Dana-Farber/Brigham and Women's Cancer Center does not recommend the routine use of HBO for the prevention or management of ORN. Adjunctive HBO may be considered for use on a case-by-case basis in patients considered to be at exceptionally high risk who have failed conservative therapy and subsequent surgical resection.

Hyperbaric oxygen therapy for maxillary bone radiation-induced injury: A 15-year single-center experience.

BACKGROUND: Although hyperbaric oxygen therapy (HBOT) is used to treat chronic radiation tissue injury, clinical evidence supporting its use in maxillary bone osteoradionecrosis (ORN) is lacking. Therefore, the purpose of this study was to report our results of collected patient outcomes from a single center's large experience using HBOT to treat maxillary bone ORN. METHODS: From 1999 to 2015, 21 patients received treatment for maxillary bone ORN at our center. The medical records were retrospectively reviewed for the following variables: age, sex, comorbidities, tumor stage and site, previous surgery, previous radiotherapy or chemoradiation therapy, HBOT data, response to treatment and further management. RESULTS: A positive clinical outcome from HBOT occurred in 85.7% of patients with ORN and was proven radiologically in 14 of 15 patients (93.3%). In 5 patients, reconstructive surgery was required thereafter. CONCLUSION: Controversy exists regarding the management of ORN of the maxillofacial skeleton. Our large, single-center experience probably supports the efficacy of HBOT for maxillary bone ORN. © 2016 Wiley Periodicals, Inc. Head Neck 39: 275-278, 2017.

Current Concepts in Osteoradionecrosis after Head and Neck Radiotherapy.

Osteoradionecrosis (ORN) of the jaws is a feared complication of head and neck radiotherapy. ORN causes significant morbidity for patients and controversy among clinicians. This overview considers the variations in definition and classification of the condition that affect estimates of incidence and also the interpretation of evidence. The influence of newer radiotherapy techniques in reducing ORN through reduced dose and xerostomia is balanced against a probable increase in a vulnerable population through a rising head and neck cancer incidence. Theories of pathophysiology of ORN include radiation-induced osteomyelitis, hypoxic and hypovascular theory and fibroatrophic theory. Prevention strategies include restorative dentistry and radiation planning techniques. Treatments range from conservative 'watch and wait' through to more radical surgical strategies. Newer medical management strategies are available with a limited evidence base. The use of hyperbaric oxygen therapy remains controversial and the background and need for newer hyperbaric oxygen trials is discussed.

Rib fractures after reirradiation plus hyperthermia for recurrent breast cancer: Predictive factors.

BACKGROUND: Combining reirradiation (reRT) and hyperthermia (HT) has shown high therapeutic value for patients with locoregional recurrent breast cancer (LR). However, additional toxicity of reirradiation (e.g., rib fractures) may occur. The aim of this study is to determine the impact of potential risk factors on the occurrence of rib fractures. PATIENTS AND METHODS: From 1982-2005, 234 patients were treated with adjuvant reRT + HT after surgery for LR. ReRT consisted typically of 8 fractions of 4 Gy twice a week, or 12 fractions of 3 Gy four times a week. A total of 118 patients were irradiated with abutted photon and electron fields. In all, 60 patients were irradiated using either one or alternating combinations of abutted AP electron fields. Hyperthermia was given once or twice a week. RESULTS: The 5-year infield local control (LC) rate was 70 %. Rib fractures were detected in 16 of 234 patients (actuarial risk: 7 % at 5 years). All rib fractures occurred in patients treated with a combination of photon and abutted electron fields (p = 0.000); in 15 of 16 patients fractures were located in the abutment regions. The other significant predictive factors for rib fractures were a higher fraction dose (p = 0.040), large RT fields, and treatment before the year 2000. DISCUSSION AND CONCLUSION: ReRT + HT results in long-term LC. The majority of rib fractures were located in the photon/electron abutment area, emphasizing the disadvantage of field overlap. Large abutted photon/electron fields combined with 4 Gy fractions increase the number of rib fractures in this study group. However, as these factors were highly correlated no relative importance of the individual factors could be estimated. Increasing the number of HT sessions a week does not increase the risk of rib fractures.

Management of complications and compromised free flaps following major head and neck surgery.

Microvascular free flaps are preferred for most major head and neck reconstruction surgeries because of better functional outcomes, improved esthetics, and generally higher success rates. Numerous studies have investigated measures to prevent flap loss, but few have evaluated the optimal treatment for free flap complications. This study aimed to determine the complication rate after free flap reconstructions and discusses our management strategies. Medical records of 260 consecutive patients who underwent free flap reconstructions for head and neck defects between July 2006 and June 2010 were retrospectively reviewed for patient and surgical characteristics and postoperative complications. The results revealed that microvascular free flaps were extremely reliable, with a 3.5 % incidence of flap failure. There were 78 surgical site complications. The most common complication was neck wound infection, followed by dehiscence, vascular congestion, abscess, flap necrosis, hematoma, osteoradionecrosis, and brisk bleeding. Twenty patients with poor wound healing received hyperbaric oxygen therapy, which was ineffective in three patients who eventually experienced complete flap loss. Eleven patients with vascular congestion underwent medicinal leech therapy, which was effective. Among the 78 patients with complications, 44 required repeat surgery, which was performed for postoperative brisk bleeding in three. Eventually, ten patients experienced partial flap loss and nine experienced complete flap loss, with the latter requiring subsequent pectoralis major flap reconstruction. Microvascular free flap reconstruction represents an essential and reliable technique for head and neck defects and allows surgeons to perform radical resection with satisfactory functional results and acceptable complication rates.

The management of osteoradionecrosis of the jaws--a review.

PURPOSE: To review the conservative and surgical management options of osteoradionecrosis, in particular, highlighting the recent the use of anti-radiation fibrosis drugs (pentoxifylline, tocopherol and clodronate). MATERIAL AND METHODS: We performed a literature review. The management options were divided into two groups, conservative and surgical management. RESULTS: Over the years several treatment options have been proposed including; conservative management (antibiotics, analgesics, oral hygiene), ultrasound therapy, hyperbaric oxygen therapy, surgical resection with reconstruction and more recently the use of anti-radiation fibrosis drugs (pentoxifylline, tocopherol and clodronate). Early or low grade ORN can be managed conservatively using a combination of treatment options. In advanced or refractory cases of ORN (pathological fracture, orocutaneous fistula) surgical treatment, at present, remains the only treatment option available. A new understanding of the pathophysiology of ORN (radiation induced fibroatrophic process) has lead to the development of new therapeutic management regimes. CONCLUSION: In advanced or refractory cases of ORN surgical treatment, including microvascular reconstructive techniques for bone and soft tissue, remains the only option available.

Osteoradionecrosis of the temporal bone: a case series.

OBJECTIVE: To study osteoradionecrosis (ORN) of the temporal bone. STUDY DESIGN: Retrospective case review. SETTING: Academic medical center. PATIENTS: Patients were included who had previously undergone radiation to the head and neck and then developed exposed necrotic bone within the ear canal that persisted at least 3 months. INTERVENTIONS: Patients were treated with a variety of modalities, including conservative therapy with antibiotic ear drops and in-office debridements, hyperbaric oxygen therapy, and surgery. MAIN OUTCOME MEASURES: To describe the presentation and management of patients with temporal bone osteoradionecrosis. RESULTS: Thirty-three patients with temporal bone osteoradionecrosis were included. The most common site of primary tumor was the parotid gland (n = 11), followed by the nasopharynx (n = 7). The time to development of ORN varied between 1 and 22 years, with mean of 7.9 years. The mean radiation dose was 62.6 Gy to the primary tumor, 53.1 Gy to the affected temporal bone, and 65.2 Gy to the affected tympanic bone. The most common symptoms of ORN were otorrhea (n = 15), hearing loss (n = 13), and otalgia (n = 12). Fifteen patients had bacterial superinfection, most commonly Staphylococcus aureus (n = 9). Conservative therapy was successful at managing symptoms but not in eradicating exposed bone in most patients. Surgery was used for recalcitrant pain, infection, cholesteatoma, cranial neuropathies, and intracranial complications. CONCLUSION: Osteoradionecrosis is a rare complication of radiation to the temporal bone. Management should be aimed at relief of symptoms, eradication of superinfection, and treatment of other commonly present radiation effects like cholesteatoma and hearing loss.

Comparison of complications in free flap reconstruction for osteoradionecrosis in patients with or without hyperbaric oxygen therapy.

BACKGROUND: Hyperbaric oxygen (HBO) therapy induces native tissue oxygenation. The hypothesis was patients with mandibular osteoradionecrosis (ORN) and a history of HBO therapy would have less free flap reconstruction complications than patients without HBO therapy. METHODS: We conducted a multisite retrospective review involving radical debridement and free flap reconstruction for ORN between January 1, 1995 and June 30, 2011. Patients were stratified based on receiving prior HBO therapy or not. RESULTS: Thirty-nine of 89 patients (43.8%) had HBO therapy whereas 50 of 89 (56.2%) did not. The HBO therapy group had significantly less patients with diabetes. There was no statistical difference in overall complication in patients between groups (p = .5478). However, there was marginal significance of increased infections in the patients with a history of HBO therapy (p = .0545). CONCLUSION: Although no significant differences in free flap reconstruction complication rates were observed between these 2 patient cohorts, there was marginal significance of increased infections in the patients with a history of HBO therapy. A prospective multi-institutional randomized study examining issues of infection would address issues inherent in this retrospective study.

Sternoclavicular osteoradionecrosis following treatment for head and neck cancer.

Osteoradionecrosis (ORN) is a well described complication of radiation therapy (RT) for head and neck cancer (HNC), with a past reported incidence as high as 10-18% [1,4] mostly involving the mandible. ORN rarely involves the sternoclavicular complex in HNC patients treated with RT. Here, we present a case of HNC treated with combined (cytotoxic) chemotherapy and radiation therapy (CCRT) complicated by ORN and osteomyelitis of the sternoclavicular complex involving large segments of both clavicles, the sternum, and the trachea.