Prevention and Management of Osteoradionecrosis in Patients With Head and Neck Cancer Treated With Radiation Therapy: ISOO-MASCC-ASCO Guideline.

PURPOSE: To provide evidence-based recommendations for prevention and management of osteoradionecrosis (ORN) of the jaw secondary to head and neck radiation therapy in patients with cancer. METHODS: The International Society of Oral Oncology-Multinational Association for Supportive Care in Cancer (ISOO-MASCC) and ASCO convened a multidisciplinary Expert Panel to evaluate the evidence and formulate recommendations. PubMed, EMBASE, and Cochrane Library databases were searched for randomized controlled trials and observational studies, published between January 1, 2009, and December 1, 2023. The guideline also incorporated systematic reviews conducted by ISOO-MASCC, which included studies published from January 1, 1990, through December 31, 2008. RESULTS: A total of 1,539 publications were initially identified. There were 487 duplicate publications, resulting in 1,052 studies screened by abstract, 104 screened by full text, and 80 included for systematic review evaluation. RECOMMENDATIONS: Due to limitations of available evidence, the guideline relied on informal consensus for some recommendations. Recommendations that were deemed evidence-based with strong evidence by the Expert Panel were those pertaining to best practices in prevention of ORN and surgical management. No recommendation was possible for the utilization of leukocyte- and platelet-rich fibrin or photobiomodulation for prevention of ORN. The use of hyperbaric oxygen in prevention and management of ORN remains largely unjustified, with limited evidence to support its practice.Additional information is available at www.asco.org/head-neck-cancer-guidelines.

The incidence of osteoradionecrosis of the jaws in oral cavity cancer patients treated with intensity-modulated radiotherapy: a systematic review and meta-analysis.

OBJECTIVE: A systematic review with meta-analysis was conducted to define the incidence of osteoradionecrosis (ORN) in patients with oral cavity cancer (OCC) treated with intensity-modulated radiotherapy (IMRT), and to identify the risk factors influencing its development. STUDY DESIGN: Six databases were searched systematically. A meta-analysis was performed to determine overall, spontaneous, and dental extraction-attributed incidences of ORN. The Grading of Recommendations Assessment, Development, and Evaluation tool evaluated evidence certainty. RESULTS: Out of 11 eligible studies, 6 underwent meta-analysis for the overall aggregated ORN incidence in OCC patients receiving IMRT, resulting in an incidence rate of 8% (95% CI: 6%-11%). Regarding development reasons, 2 studies were assessed, revealing an incidence of 36% (95% CI: 1%-98%) for spontaneous ORN, and 17% (95% CI: 5%-44%) ensued from dental extraction exclusively pre-RT. All rates had very low certainty of evidence. Factors significantly correlated with ORN development included postoperative RT use (78%), employment of therapeutic doses above 50 Gy, and mandibular involvement (80.5%). CONCLUSION: The findings suggest that IMRT alone is not sufficient to decrease ORN rates in OCC patients, underscoring the importance of precisely identifying the involved risk factors. However, further detailed primary studies will be necessary.

Development and Standardization of an Osteoradionecrosis Classification System in Head and Neck Cancer: Implementation of a Risk-Based Model.

PURPOSE: Osteoradionecrosis of the jaw (ORN) can manifest in varying severity. The aim of this study is to identify ORN risk factors and develop a novel classification to depict the severity of ORN. METHODS: Consecutive patients with head and neck cancer (HNC) treated with curative-intent intensity-modulated radiation therapy (IMRT) (≥45 Gy) from 2011 to 2017 were included. Occurrence of ORN was identified from in-house prospective dental and clinical databases and charts. Multivariable logistic regression model was used to identify risk factors and stratify patients into high-risk and low-risk groups. A novel ORN classification system was developed to depict ORN severity by modifying existing systems and incorporating expert opinion. The performance of the novel system was compared with 15 existing systems for their ability to identify and predict serious ORN event (jaw fracture or requiring jaw resection). RESULTS: ORN was identified in 219 of 2,732 (8%) consecutive patients with HNC. Factors associated with high risk of ORN were oral cavity or oropharyngeal primaries, received IMRT dose ≥60 Gy, current/ex-smokers, and/or stage III to IV periodontal condition. The ORN rate for high-risk versus low-risk patients was 12.7% versus 3.1% (P < .001) with an AUC of 0.71. Existing ORN systems overclassified serious ORN events and failed to recognize maxillary ORN. A novel ORN classification system, ClinRad, was proposed on the basis of vertical extent of bone necrosis and presence/absence of exposed bone/fistula. This system detected serious ORN events in 5.7% of patients and statistically outperformed existing systems. CONCLUSION: We identified risk factors for ORN and proposed a novel ORN classification system on the basis of vertical extent of bone necrosis and presence/absence of exposed bone/fistula. It outperformed existing systems in depicting the seriousness of ORN and may facilitate clinical care and clinical trials.

Prevalence of free flap failure in mandibular osteoradionecrosis reconstruction: a systematic review and meta-analysis.

Our study aimed to estimate the prevalence of total free flap failure following free flap reconstruction for mandibular osteoradionecrosis (mORN) and assess the impact of potential moderators on this outcome. A comprehensive systematic literature search was independently conducted by two reviewers using the Medline, Scopus, Web of Science and Cochrane Library databases. Quality assessment of the selected studies was performed, and prevalence estimates with 95% confidence intervals (CI) were calculated. Outlier and influential analyses were conducted, and meta-regression analyses was employed to investigate the effects of continuous variables on the estimated prevalence. Ultimately, forty-six eligible studies (involving 1292 participants and 1344 free flaps) were included in our meta-analysis. The findings of our study revealed a prevalence of 3.1% (95% CI 1.3-5.4%) for total free flap failure after reconstruction for mORN. No study was identified as critically influential, and meta-regression analysis did not pinpoint any potential sources of heterogeneity. These findings provide valuable insights for researchers and serve as a foundation for future investigations into the management of mandibular osteoradionecrosis and the prevention of free flap failure in this context.

Osteoradionecrosis Rates After Head and Neck Radiation Therapy: Beyond the Numbers.

PURPOSE: Osteoradionecrosis (ORN) is a severe late complication of head and neck radiation therapy shown to have profound negative effect on the quality of life of cancer survivors. Over the past few decades, improvements in radiation delivery techniques have resulted in a decrease in the incidence of ORN. However, even with modern radiation therapy techniques, ORN remains an important clinical concern. In recent literature, there is a wide range of reported ORN rates from 0% to as high as 20%. With such a high level of variability in the reported incidence of ORN, oncologists often encounter difficulties estimating the risk of this serious radiation therapy toxicity. METHODS AND MATERIALS: In this review, the authors present a summary of the factors that contribute to the high level of variability in the reported incidence of ORN. RESULTS: Variable definition, variable grading, and heterogeneity of both study inclusion criteria and treatment parameters can each significantly influence the reporting of ORN rates. CONCLUSIONS: Given numerous factors can affect the reported incidence of ORN, a thorough understanding of the clinical context behind the reported ORN rates is needed to comprehend the true risk of this important radiation therapy toxicity.

Risk factors associated with the development of osteoradionecrosis (ORN) in Head and Neck cancer patients in Ireland: A 10-year retrospective review.

BACKGROUND AND PURPOSES: To assess osteoradionecrosis (ORN) incidence in a population of Irish Head and Neck cancer (HNC) patients, and assess precipitating factors that may contribute to ORN development to aid prevention. MATERIALS AND METHODS: Review of 1050 HNC patients attending the Dental Oncology Clinic, CUDSH between 2010 and 2021 identified 47 cases of ORN. Medical, dental and radiotherapy records of these forty-seven patients were retrospectively reviewed. Patient-, tumour-, and treatment-related variables were investigated in association with osteoradionecrosis development. Analysis conducted using SPSS, Pearson's Chi-square test (p < 0.05), and ordinal regression model. RESULTS: ORN incidence was 4.4 %. Median time from radiotherapy (RT) to ORN development was 9.5 months (range 1-98.5 months). ORN development within the mandibular surgical site was significant (p <.001), presenting at a higher Notani grade (p =.002), in mid-mandibular body region (p =.028), at radiation doses ≥ 60 Gy (p =.035), due to induced causes (p =.029), and without resolution (p =.019). CONCLUSION: This is the first retrospective study of ORN in HNC patients in Ireland over 10-year period. ORN incidence was extremely low (4.4%). As patients reported high smoking/alcohol use and poor dental attendance pre-diagnosis, this suggests intensive dental intervention pre/post-diagnosis contributed to low ORN rates. Mandibular surgery pre-RT increased risk of developing ORN at the surgical site. Therefore, we recommend future treatment planning should contour the surgical site, designating it an organ at risk (OAR), assigning a dose constraint, where oncologically possible, with emphasis on reducing the hot-spot to this region; findings reinforce importance of life-long expert dental care to reduce ORN incidence.

Medial Femoral Condyle Periosteal Free Flap for Bone Coverage Following Debridement of Intermediate-Stage Osteoradionecrosis of the Jaw.

STUDY DESIGN: Case report. Osteoradionecrosis (ORN) of the jaw is a potentially devastating consequence of head and neck irradiation. The progression of ORN can lead to loss of bone, teeth, soft tissue necrosis, pathologic fracture, and oro-cutaneous fistula. Reconstructive surgery has mostly been reserved for late-stage disease where segmental resections are frequently necessary. Evidence is emerging to support earlier treatment in the form of debridement in combination with soft tissue free flaps for intermediate-stage ORN. The authors present a case of a 76-year-old male with persistent Notani 2 ORN of the mandible, treated with surgical removal of all remaining mandibular teeth, transoral debridement of all necrotic mandibular bone, and bone coverage with a left medial femoral condyle (MFC) periosteal free flap based on the descending genicular artery. Treatment was uneventful both intraoperatively and postoperatively. Since surgery (15 mo) the patient has remained free from clinical and radiologic signs of ORN. The MFP periosteal free flap provided an excellent result with minimal surgical complexity and morbidity in this case. Such treatment at an intermediate stage likely results in a reduction in segmental resections, less donor site morbidity, less operative time, less overall treatment time, and possibly fewer postoperative complications compared with the status quo.

Cranioplasty is not required in the reconstruction of small combined scalp and calvarial defects.

BACKGROUND: Treatment of scalp malignancies may include the need for craniectomy. The decision to perform cranioplasty is not straightforward and is frequently subjective. The purpose of this study was to assess the clinical outcomes after reconstruction of complex scalp and calvarial defects by comparing patients with and without cranioplasty. METHODS: Retrospective review of the clinical records of a consecutive series of patients who underwent scalp soft tissue reconstruction after craniectomy for malignancy or osteoradionecrosis between 2014 and 2022 at Royal Melbourne Hospital was conducted. Demographics, previous treatments, surgical details, and post-operative complications were assessed. Traumatic injuries and decompressive craniectomies were excluded. Minimum follow-up of 6 months. RESULTS: Thirty-seven patients were included in the study. Indications for surgery included skin malignancies, osteoradionecrosis, or both. There was one reconstructive failure (in the non-cranioplasty group). Infection and metalware exposure were common complications in patients who underwent cranioplasty (38.5%). No patient developed neurological symptoms subsequent to craniectomy. One patient needed revision surgery due to esthetic reasons (cranioplasty group). Transposition flaps were associated with more complications and revision procedures. CONCLUSION: Combined scalp and calvarial defects pose a difficult reconstructive challenge. Stable soft tissue coverage is more reliably achieved with free flap reconstruction. Cranioplasty is not always mandatory and should be reserved for cases with a very large bony defect or when the defect is located in a cosmetically sensitive area.

Osteoradionecrosis in a Torus Mandibularis Treated by Antimicrobial Photodynamic Therapy: A Case Report.

Background: Osteoradionecrosis (ORN) of the jaws is a late complication after radiotherapy to head and neck cancer. Objective: To describe a rare case of ORN of the torus mandibularis that was successfully managed exclusively with antimicrobial photodynamic therapy (aPDT). Case report: A 72-year-old man presented an exposed necrotic bone observed in the torus mandibularis, extending to the lingual alveolar ridge with no edema nor suppuration. The treatment provided a noninvasive treatment leading to spontaneous sequestrectomy of the torus in 2 weeks with complete mucosal repair in 5 weeks and absence of lesion signs and/or symptoms even after 6 months of follow-up. Conclusions: The aPDT indicated to be a satisfactory treatment for ORN affecting torus mandibularis, a region with surgical limitations, avoiding surgery.

Pre-chemoradiotherapy high platelet counts predict jaw osteoradionecrosis in locally advanced nasopharyngeal carcinoma patients.

INTRODUCTION: This retrospective study aimed to investigate if pretreatment platelet (PLT) levels can predict the risk of osteoradionecrosis of the jaw (ORNJ) in patients with locally advanced nasopharyngeal carcinoma (LA-NPC) who received concurrent chemoradiotherapy (CCRT). MATERIAL &METHODS: ORNJ instances were identified from LA-NPC patients' pre- and post-CCRT oral exam records. All pretreatment PLT values were acquired on the first day of CCRT. Receiver operating characteristic curve analysis was used to determine the optimal PLT cutoff that divides patients into two subgroups with distinctive ORNJ rates. The primary outcome measure was the association between pretreatment PLT values and ORNJ incidence rates. RESULTS: The incidence of ORNJ was 8.8 % among the 240 LA-NPC patients analyzed. The ideal pre-CCRT PLT cutoff which divided the patients into two significantly different ORNJ rate groups was 285,000 cells/µL (PLT ≤ 285,000 cells/µL (N = 175) vs. PLT > 285,000 cells/µL (N = 65)). A comparison of the two PLT groups revealed that the incidence of ORNJ was substantially higher in patients with PLT > 285,000 cells/L than in those with PLT≤285,000 cells/L (26.2% vs. 2.3 %; P < 0.001). The presence of pre-CCRT ≥3 tooth extractions, any post-CCRT tooth extractions, mean mandibular dose ≥ 34.1 Gy, mandibular V57.5 Gy ≥ 34.7 %, and post-CCRT tooth extractions > 9 months after CCRT completion were also associated with significantly increased ORNJ rates. A multivariate Cox regression analysis demonstrated that each characteristic had an independent significance on ORNJ rates after CCRT. CONCLUSION: An affordable and easily accessible novel biomarker, PLT> 285,000 cells/L, may predict substantially higher ORNJ rates after definitive CCRT in individuals with LA-NPC.

Retrospective study evaluating dental side effects of radiotherapy in patients treated for head and neck cancer.

INTRODUCTION: Head and neck cancer squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide with around 600,000 new diagnosis each year. Nowadays, in locally advanced disease, radiotherapy (RT) play an important role, this with or without chemotherapy in organ preservation strategies. More specific for early stage localized disease, RT (or surgery) seems to give similar results on locoregional control (LRC) and choice is made according to the organ preservation issue. Despite the fact that technical improvements have been made to optimize the radiation dose delivery and minimize the normal tissue toxicity, RT is associated with potential early and late toxicities. Osteoradionecrosis of the jaw (ORNJ), especially seen after teeth extraction, is one of the associated toxicities and can significantly impair the patient's quality of life. Because of the fear of developing ORNJ, one is very reluctant to extract or place a dental implant post-radiotherapy, especially in high irradiation dose zones (>40 Gy). Hence, it is important to define teeth at risk of future extraction before initiating RT and to handle those in high-risk irradiation zones. In order to optimise extractions, we created a predictive model of the expected irradiation dose, and thus the need for extraction, to the teeth bearing bones. The aim of this study is to validate our model and to define the potential relationship between the radiation dose received by each tooth and the dental complications observed. MATERIAL AND METHODS: Between March 2012 and March 2018, patients with HNSCC treated by intensity modulated RT were retrospectively analysed. The mean irradiation dose for each tooth was generated on the administered treatment plan by contouring each tooth separately on each dosimetric scan section using dedicated software (Eclipse, Varian). In order to validate our predictive model, we compared the actual generated/administered teeth irradiation doses with the irradiation doses predicted by our model. RESULTS: Our predictive model was accurate in 69.6% of the cases. In 12.5% of cases the predicted dose was higher than the calculated dose and lower in 17,8% of the cases. A correct- or over-estimation (is the latter being clinically less worrying than an underestimated dose) was achieved in 82% of cases. For the 18% of cases underfitting, the mean margin of error was 5.7 Gy. No statistically significant association was found between the development of caries and doses to the teeth, doses to the parotid glands or dental hygiene. However, a significant association between dental irradiation at more than 40 Gy and the occurrence of dental fractures (p = 0.0002) were demonstrated. CONCLUSIONS: Our predictive model seems to be 82% accurate for dose prediction, hence might be helpful for optimizing/minimizing prophylactic extractions. Indeed, following our model, professionals could decide not to extract damaged teeth in areas not at risk of ORNJ, lowering morbidity during and after RT. Contrary to the literature, no relationship was found between the occurrence of dental caries and parotid irradiation and the patient's oral hygiene. However, for the first time, a highly significant correlation between the occurrence of dental fracture and dental irradiation at more than 40 Gy was observed.

[Prevention, diagnosis and management of osteoradionecrosis: Where do we stand?] / Prévention, diagnostic et prise en charge de l'ostéoradionécrose : où en est-on ?

Osteoradionecrosis (ORN) is a late secondary iatrogenic complication of external radiotherapy for cancers of the upper aero-digestive tract. Despite the systematization of intensity-modulated radiotherapy and its potential for preserving salivary secretion and limiting the dose delivered to the supporting bone, ORN remains a feared and frequent complication. The objective of this literature review was to provide an overview of the management of ORN and to determine the key points that would make it possible to improve patient care. The diagnosis of ORN requires to eliminate tumor recurrence then is based on clinical arguments and imaging by CT or Cone Beam evolving in a chronic mode (more than 3-6 months). The harmonization of its classifications aims to offer comprehensive and multidisciplinary care as early as possible. Primary prevention is based on pre-therapeutic oral and dental preparation, then associated with fluoroprophylaxis if salivary recovery is insufficient and requires supervision of invasive dental care and prosthetic rehabilitation. Semi-automatic contouring tools make it possible to identify doses delivered to dental sectors and guide dental care with personalized dosimetric mapping. Conservative medical treatment is offered at an early stage where innovative medical treatments, highlighted by early studies, could be of interest in the future. In the event of advanced ORN, a non-conservative treatment is then proposed and frequently consists of interruptive mandibulectomy associated with reconstruction by bony free flap, the conditions of implantation remaining to be defined with the support of prospective clinical trials.

[Issues and implementation of postoperative radiotherapy after flap reconstructive surgery in head and neck cancers]. / Enjeux et mise en œuvre de radiothérapie postopératoire après chirurgie reconstructrice avec lambeau dans les cancers de la tête et du cou.

The management of head and neck cancers is multidisciplinary, often relying on the use of combined treatments to maximize the chances of cure. Combined treatments are however also responsible for cumulative side effects. The aim of reconstructive surgery with a flap is to restore a function lost with the loss of substance from the tumor resection. However, changes in reconstructive surgery have impact of postoperative radiotherapy planning. The optimization of imaging protocols for radiotherapy planning should make it possible to identify postoperative changes and to distinguish flaps from surrounding native tissues to delineate the flaps and document the spontaneous evolution of these flaps or dose-effect relationships in case of radiotherapy. Such changes include atrophy, fibrosis of soft tissue flaps and osteoradionecrosis of bone flaps. Radiotherapy optimization also involves standardization of the definition of target volumes in situations where a flap is present, a situation that is increasingly common in routine care. This evolution of practice, beyond the essential multidisciplinary consultation meetings defining treatment indications, requires a close radio surgical collaboration with respect to technical aspects of the two disciplines. Doing so, anticipation of relapse and toxicity profiles could possibly lead to propose strategies for personalized de-escalation of multimodal treatments through interdisciplinary trials.

Favorable effects of open surgery on patients with extensive skull base osteoradionecrosis through a personalized sequential approach: A case series.

The present study aimed to investigate outcomes following open surgery for extensive skull base ORN. Open surgery through a personalized sequential approach was employed to deal with five cases of extensive skull base ORN. Two patients with mild cases underwent regional debridement and sequestrectomy, and three patients with severe cases underwent extensive resection with reconstruction using free anterolateral thigh (ALT) flap. Biological glues and vascularized flaps were used for obturation of the skull base bony defect to prevent postoperative cerebrospinal fluid (CSF) leakage. The infections were controlled by antibiotic administrations which strictly followed the principles of antimicrobial stewardship (AMS). As results, both regional debridement plus sequestrectomy and extensive resection achieved satisfied outcomes in all patients. No severe complications and delayed hospitalization occurred. During the follow-up period (8-19 months), all patients were alive, pain free, without crusting or purulent discharge, and no sequestration or CSF leakage occurred. In conclusion, a personalized sequential approach including open surgery, pedicled/vascularized free flap reconstruction and AMS was advocated for patients with extensive skull base ORN.

Investigation of clindamycin concentrations in human plasma and jawbone tissue in patients with osteonecrosis of the jaw: A prospective trial.

The aim of this study was to investigate the jawbone concentration of clindamycin (CLI) in patients with an osteonecrosis of the jaw (ONJ). Patients with medication-related ONJ (MRONJ) and osteoradionecrosis (ORN) with an antibiotic treatment with CLI were included. Plasma, vital and necrotic bone samples were collected. Plasma and jawbone samples were analyzed by liquid chromatography-tandem mass spectrometry. Patients with MRONJ exhibited a mean plasma CLI concentration of 9.6 µg/mL (SD ± 3.6 µg/mL) and mean concentrations of 2.3 µg/g CLI (SD ± 1.4 µg/g) and 2.1 µg/g CLI (SD ± 2.4 µg/g) in vital and necrotic bone samples, without statistical significance (p = 0.79). In patients with ORN, mean concentration in plasma was 12.0 µg/mL (SD ± 2.6 µg/mL), in vital bone 2.1 µg/g (SD ± 1.5 µg/g), and in necrotic bone 1.7 µg/g (SD ± 1.2 µg/g). Vital and necrotic bone concentrations did not differ significantly (p = 0.88). The results demonstrate that CLI concentrations are considerably lower than in plasma, but sufficient for most bacteria present in ONJ. Within the limitations of the study, it seems that CLI is a relevant alternative to other antibiotics in the treatment of ONJ because it reaches adequate concentrations in jawbone.