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Research Frontiers in Oral Toxicities of Cancer Therapies: Osteoradionecrosis of the Jaws

Research Frontiers in Oral Toxicities of Cancer Therapies: Osteoradionecrosis of the Jaws Abstract The deleterious effects of head and neck radiation on bone, with osteoradionecrosis (ORN) as the major disabling side effect of head and neck cancer treatment, are difficult to prevent and hard to treat. This review focuses on the current state of the science regarding the pathobiology, clinical impact, and management of ORN. With regard to the pathobiology underlying ORN, it is not yet confirmed whether the current radiation schedules by 3-dimensional conformal radiotherapy and intensity modified radiotherapy result in an unchanged, decreased, or increased risk of developing ORN when compared with conventional radiation treatment, the main risk factor being the total radiation dose delivered on any clinically significant surface of the mandible. With regard to the prevention of ORN, a thorough, early pre-irradiation dental assessment is still considered the first step to reduce the hazard of developing ORN post-radiotherapy, and hyperbaric oxygen (HBO) treatment reduces the risk of developing ORN in case of dental surgery in an irradiated field. With regard to the treatment of ORN, the focus is bidirectional: elimination of the necrotic bone and improving the vascularity of the normal tissues that were included in the radiation portal. The cure rate of limited ORN by conservative therapy is approximately 50%, and the cure rate of surgical approaches when conservative therapy has failed is approximately 40%. Whether it is effective to support conservative or surgical treatment with HBO as an adjuvant is not set. HBO treatment is shown to increase the vascularity of hard and soft tissues and has been reported to be beneficial in selected cases. However, in randomized clinical trials comparing the preventive effect of HBO on developing ORN with, eg, antibiotic coverage in patients needing dental surgery, the preventive effect of HBO was not shown to surpass that of a more conservative approach. More recently, pharmacologic management was introduced in the treatment of ORN with success, but its efficacy has to be confirmed in randomized clinical trials. The major problem of performing well-designed randomized clinical trials in ORN is having access to large numbers of patients with well-defined, comparable cases of ORN. Because many institutions will not have large numbers of such ORN cases, national and international scientific societies must be approached to join multicenter trials. Fortunately, the interest of funding organizations and the number researchers with an interest in healthy aging is growing. Research aimed at prevention and reduction of the morbidity of cancer treatment fits well within these programs. Approximately 75% of patients with head and neck cancer need radiotherapy as a primary treatment, as an adjunct to surgery, in combination with chemotherapy or as palliation (1–3). Of these patients, 50% will be long-term survivors for whom a low level of treatment morbidity is of major importance. Clinically significant nonosseous late effects of head and neck radiation are well documented in the literature and include xerostomia, compromised swallowing and speech, and increased risk for developing dental caries and oral infections (4,5). These toxicities can collectively have a negative impact on patients’ quality of life. Of note, however, is that the deleterious effects of head and neck radiation on bone are among the hardest to treat and most disabling side-effects of head and neck cancer treatment (6). When osteoradionecrosis (ORN) of the maxilla or mandible occurs, progression of ORN can be difficult to control, and resultant large osseous defects may develop (Figure 1). Figure 1. Open in new tabDownload slide Osteoradionecrosis of the mandible in an edentulous patient treated for a T3N2b squamous cell carcinoma of the floor of the mouth, 1 year after ablative surgery and intensity modified radiotherapy. Figure 1. Open in new tabDownload slide Osteoradionecrosis of the mandible in an edentulous patient treated for a T3N2b squamous cell carcinoma of the floor of the mouth, 1 year after ablative surgery and intensity modified radiotherapy. ORN is defined as bone death secondary to radiotherapy and is characterized by a nonhealing area of exposed bone (7–9). A wide range of clinical presentations and symptoms is associated with ORN, from asymptomatic exposed bone to more advanced stages of ORN that frequently present with severe pain and infection of the bone requiring surgical resection and reconstruction for management (Figure 2) (6,10). Moreover, it is not yet confirmed whether the replacement of the more conventional radiation schedules by 3D conformal radiotherapy and intensity modified radiotherapy (IMRT) result in an unchanged, decreased, or increased risk of developing ORN. The main risk factor for developing ORN is the cumulative radiation dose received by any clinically significant volume of the mandible. Figure 2. Open in new tabDownload slide Severe osteoradionecrosis after treatment of a T4N2b squamous cell carcinoma of the gingiva and floor of mouth with ablative and reconstructive surgery with a free vascularized transplant and postoperative intensity modified radiotherapy. Figure 2. Open in new tabDownload slide Severe osteoradionecrosis after treatment of a T4N2b squamous cell carcinoma of the gingiva and floor of mouth with ablative and reconstructive surgery with a free vascularized transplant and postoperative intensity modified radiotherapy. Pathobiological mechanisms underlying late radiation injuries of the jawbone have not yet been fully established. Presumably, late damage to bone and its supportive tissues is characterized by a density reduction of small blood vessels and replacement of normal tissue cells with fibrous tissue (5,11–15). Due to the resulting insufficient oxygen supply to sustain normal function, this progressive and delayed radiation damage may reach a critical point where the tissue breaks down to form an area of cell death (soft tissue necrosis with or without ORN). This review focuses on the current state of the science regarding the pathobiology, clinical impact, and management of ORN. New research directions for the field are indicated, based on current gaps in mechanism as well as new treatment strategies. The following key research questions will be addressed in the next paragraphs: What is the mechanism underlying development of ORN of the jaws? Among others, does ORN result from radiation injury to the bone modeling system and/or to the vascular system, or is it the result of fibro-apoptotic bone changes? Has the risk on developing ORN of the jaws been changed by the introduction of IMRT and/or concurrent chemotherapy in the radiation treatment of head and neck tumors? And what about even newer radiation techniques, eg, protons that allow for a superior dose distribution due to a more targeted location of the maximum deposited energy dose? Can development of ORN of the jaws be prevented? Among others, is there any evidence that pretreatment oral examination followed by removal of oral foci of infection is prophylactic, and is there a need for hyperbaric oxygen (HBO) and/or antibiotics when needing oral surgery in irradiated jaws? How should ORN of the jaws be managed when it has developed? In other words, when should it be addressed conventionally and when is there a need for antibiotics, surgery, and/or HBO? And what about pharmacologic management of ORN? Pathobiology: Current Paradigm and New Frontiers Head and Neck Radiation The goal in radiotherapy is to maximize the biological effect of radiation on the tumor while limiting its toxic effects on normal tissues. Tolerance of the adjacent normal tissues is the most important dose-limiting factor in radiotherapy. Therefore, treatment is administered over several sessions to give the normal tissue time to recover because normal tissue has better damage-repair capabilities than tumor cells (16). Depending on stage and location of the primary tumor and (potentially) affected lymph nodes, the oral cavity, salivary glands, and jawbones of most head and neck cancer patients are at least to some extent located in the radiation portals. Thus, even with the most optimal fractionation schedule and radiation techniques, unwanted radiation-induced changes will occur in these tissues (3,5,11,12,17,18). The indicated cumulative radiation dose is based on location and type of malignancy and whether radiotherapy will be given alone or in combination with other modalities. Most patients with head and neck cancers, treated with a curative intent, receive a cumulative dose between 46 and 70 Gy. This dose is usually administered during a 5- to 7-week period, once a day, five to six times a week with 2 Gy per fraction (3,13,16). Several strategies to further increase locoregional tumor control without increasing the normal tissue complication probability has been developed and tested in clinical trials or are already implemented in daily clinical practice, including among others a 10% dose escalation with dose redistribution to increase tumor control probability. Currently, IMRT, either with or without concomitant chemotherapy, is most applied (3). In IMRT, computer-controlled photon accelerators distribute precise radiation doses to the tumor. The applied radiation dose is consistent with the 3-dimensional (3D) shape of the tumor by controlling, or modulating, the radiation beam’s intensity. The aim of this approach is to elevate the cumulative radiation dose near the gross tumor volume while decreasing the radiation to neighboring normal tissues to a minimum. Compared with conventional radiation therapy and 3D conformal radiotherapy, critical normal tissues can be spared to a greater extent (19–21). Comparison of the incidence of ORN after IMRT or conventional radiotherapy shows statistically significant differences (22). It has been suggested that higher mandibular radiotherapy dose volumes are related to higher incidence of ORN (23). Lower dose volumes in the mandible could be obtained by IMRT with the tumor adequately treated. Proton therapy generates an even more exquisite dose distribution in some patients, thus potentially further improving patient outcomes (3). IMRT and proton therapy are also thought to reduce long-term morbidity, especially damage to the salivary glands and ORN. Radiation and Bone The classic modeling for ORN published by Marx (24) includes the concept that radiation to the jaw leads to long-term biological changes including vasculature impairment, hypoxia, and impaired wound recovery and secondary infection. Alterations in bone matrix after irradiation develop relatively slowly, whereas it is thought that the initial changes in bone result from injury to the remodelling system (osteocytes, osteoblasts, and osteoclasts) and alterations of the vascular system become apparent later (25,26). Another hypothesis cites fibroapoptotic bone changes (12). In that hypothesis, bone and soft tissue damage is thought to result from radiation-induced fibrosis; acute radiation-induced inflammation with endothelial changes is followed by abnormal fibroblast activity with extra-cellular matrix disruption and finally late fibroatrophy. When fibroatrophy occurs, healed tissues are fragile and undergo late reactivation of the acute inflammatory response after injury (12,27). In addition to the effects on fibroblasts, osteoblasts tend to be more radiosensitive than osteoclasts; a relative increase in the lytic activity may thus occur. Whether the altered bone remodelling activity is the result of direct irradiation injury to the cells of the remodelling system, the indirect result of irradiation-induced vascular injury, or a combination of both phenomena is still a matter of debate. Is it involvement of osteoblasts, involvement of fibroblasts, or a combination of both? Radiation injury to the fine vasculature of bone and its surrounding tissues first leads to hyperaemia, followed by endarteritis, thrombosis, and a progressive occlusion and obliteration of small vessels. Within bone this results in further reduction of cell number and progressive fibrosis. With time the marrow exhibits marked acellularity and hypo- or avascularity, with significant fibrosis and fatty degeneration. Some lacunae may become devoid of osteocytes. The endosteum atrophies with clinically significant loss of active osteoblasts and osteoclasts. The periosteum demonstrates significant fibrosis, with a similar loss of remodelling elements (7,9,25,26,28–31). In 2012, Marx and Turson (13) reported that necrotic bone was present in all studied ORN specimens as evidenced by empty osteocytic lacunae, absence of osteoblastic rimming, and empty Haversian systems and Volkmann canals. Moreover, there was a notable absence of inflammatory cells and normal marrow elements or fat cells throughout the marrow. Bone marrow primarily consisted of acellular collagen, with only a rare cell nuclei noted. Of a greater clinical impact is their observation of an absence of functioning blood vessels in all studied specimens. Remnants of old blood vessels were observed as devoid of endothelial and adventitial cells, leaving only a ring of basal lamina. Microorganisms were present in about one-half of the studied specimen on the surface of the bone. Periosteum was also preserved in about one-half of the studied specimens, but that periosteum was seen to be acellular and avascular. Thus, the histopathological evidence reported by Marx and Turson (13) supports a physical injury to bone and the soft tissues covering bone from the high linear energy transfer of radiotherapy underlying the development of ORN. In contrast to bisphosphonate osteonecrosis, in ORN no osteoclastic impairment underlies the development of ORN, but ORN is the result of direct injury to all cell populations in the field of radiation. Unlike in bisphosphonate osteonecrosis, radiation has directly damaged the blood supply, the periosteum, and the overlying mucosa (Figure 3) (32). Figure 3. Open in new tabDownload slide Current insights in pathobiological process of osteoradionecrosis [modified from Lyons et al. (32)]. Figure 3. Open in new tabDownload slide Current insights in pathobiological process of osteoradionecrosis [modified from Lyons et al. (32)]. In a prospective imaging trial, the effect of radiotherapy on bone perfusion was demonstrated with a dynamic contrast-enhanced MRI. With this technique, dose-dependent alterations in mandibular bone vascularity during chemoradiotherapy could be observed (33). The studied biomarkers were physiological correlates of acute mandibular vascular injury and recovery temporal kinetics. Further validation of these parameters for prediction and detection of late radiotherapy mandibular sequelae is warranted. Prevalence of ORN In a systematic review by Peterson et al. (34), the prevalence of ORN was assessed by type of radiation therapy. Taking into account quality measures of published studies, the weighted prevalence of ORN was found to be 7.3% (95% confidence interval [CI] = 4.8% to 10%) for conventional radiotherapy, but there is a great variety between the studies reporting prevalence rates with prevalence up to 25.5% (7,14,35–38). The incidence of osteonecrosis of the maxilla is much lower than in the mandible (38–40). Moreover, it has been reported that the prevalence of ORN is less with IMRT at 5.2% (95% CI = 0.0% to 12.0%) (34). However, there are also recent indications that the risk might increase as treatment of head and neck cancer with IMRT might result in unwanted radiation exposure to the whole mandible bone (41) and ORN rates were shown to be rather high when IMRT was combined with bone resection (20). Particularly, mandibular molar regions for base of tongue, tonsil, and hypopharynx cancers were shown to receive higher IMRT doses on average, posing the greatest ORN risk (42). Finally, a recent study in a large cohort of patients revealed that the time frame to develop jaw complications after IMRT apparently has a longer latency, but with time the risk of developing ORN (25.5% after median follow-up of 3.4 years) is similar to that of non-IMRT treatment (25%, 1.2 years; in that study, 25.5% after a median follow-up of 3.4 years) (37). ORN following dental extractions post-radiotherapy occurs in upward of 50% of cases (43); therefore, pre-radiation oral evaluation and dental management of potential odontogenic or periodontal infections is vital. Spontaneous ORN, which has been reported to occur in almost 35% of all cases of ORN, is related to increased age, higher body mass index, use of steroids, smoking, high radiation dose (>65 Gy), field of radiation (volume of the mandible included in the field and proximity of maximal dosing to bone), hyperfractionation, use of radiation implant sources too close to the bone, and combined interstitial and external beam irradiation (7,9,24,37–40,44–48). The spontaneous form of ORN represents a greater outright cellular kill of normal tissue elements and an inability of soft and hard tissue to keep up with cellular turnover and collagen synthesis. This type of necrosis usually occurs within the first 2 years after radiotherapy (6,9,19,24,38,47), but it can occur at any time later after irradiation (8,36,38). Clinical Management: Successes and Barriers Prevention of ORN Besides improved radiotherapeutic modalities and shielding, the first step toward prevention of ORN has been presumed to be a thorough, early pre-irradiation dental assessment (Table 1) (49). This pretreatment oral examination should attempt to identify the main factors that will increase the risk for ORN. On the basis of this inventory, steps may be taken to control or eliminate as many factors as is practical before radiotherapy begins (7,14,38,45,49–57). The primary goal should be to optimize the condition of the patient’s dentition to confirm that high-risk procedures (extraction or surgical removal of teeth, apicoectomies) will not have to be performed in the post-irradiation period (28–30,38–40,45,50–53,57,58). To maximize the impact of screening, adequate time for treatment and healing must be allowed (51,52). Screening is of limited value if the inventory of oral foci of infection is performed too close to the start of radiation therapy, which will preclude dental intervention. Pre-irradiation extraction followed by inadequate healing time is known to predispose to ORN (7,9,37,40,58). Table 1. Treatment of oral foci of infection within or outside the radiation field Assessed tooth problems . Cumulative dose > 40Gy . Cumulative dose < 40 Gy or outside the radiation portal . Caries profunda Tooth extraction Restoration, if necessary combined with endodontic treatment, or tooth extraction Periapical pathosis (on radiographs) without symptoms and/or additional problems In teeth without root canal filling: In teeth without root canal filling: Endodontic treatment and/or apexification Endodontic treatment In teeth with root canal filling: In teeth with root canal filling: Endodontic re-treatment, apexification, or tooth extraction (needed in case of pre-radiotherapy time limitations) Endodontic retreatment, apexification, or tooth extraction Treatment can be postponed until after radiotherapy Extensive periapical pathosis (on radiographs) combined with periodontal disease, in afunctional teeth or with symptoms Tooth extraction In teeth without root canal filling: Endodontic treatment combined with initial periodontal treatment In teeth with root canal filling: Endodontic retreatment, apexification or tooth extraction depending on the prognosis Avital pulp with symptoms without periapical radiolucency on radiographs Endodontic treatment or tooth extraction (which might be necessary in case of pre-radiotherapy time limitations) Endodontic treatment or tooth extraction depending on the prognosis Avital pulp without symptoms and without periapical radiolucency on radiographs Endodontic treatment or tooth extraction (needed in case of pre-radiotherapy time limitations) Endodontic treatment (which can be postponed until after radiotherapy) Periodontal disease with: Pockets 4–5 mm Initial periodontal therapy Initial periodontal therapy Pockets ≥6 mm Tooth extraction Initial periodontal therapy Gingival recessions ≥ 6 mm Tooth extraction Only recession requires no treatment Furcation ≥ grade 1 Tooth extraction Initial periodontal therapy Mobility ≥ grade 1 Tooth extraction Initial periodontal therapy Impacted teeth or roots fully covered by bone without radiographic abnormalities No treatment If problems are expected in the future: tooth extraction No treatment Impacted teeth or roots not fully covered by bone or with radiographic abnormalities (eg, cysts, apical radiolucency) Tooth extraction No treatment or, in case of symptoms, surgical removal Roots with periapical radiolucency might be worth preserving by endodontic treatment and restoration (which can be postponed until after radiotherapy) Cysts Surgical removal Surgical removal Internal or external root resorption Tooth extraction Endodontic treatment or tooth extraction depending on the prognosis Assessed tooth problems . Cumulative dose > 40Gy . Cumulative dose < 40 Gy or outside the radiation portal . Caries profunda Tooth extraction Restoration, if necessary combined with endodontic treatment, or tooth extraction Periapical pathosis (on radiographs) without symptoms and/or additional problems In teeth without root canal filling: In teeth without root canal filling: Endodontic treatment and/or apexification Endodontic treatment In teeth with root canal filling: In teeth with root canal filling: Endodontic re-treatment, apexification, or tooth extraction (needed in case of pre-radiotherapy time limitations) Endodontic retreatment, apexification, or tooth extraction Treatment can be postponed until after radiotherapy Extensive periapical pathosis (on radiographs) combined with periodontal disease, in afunctional teeth or with symptoms Tooth extraction In teeth without root canal filling: Endodontic treatment combined with initial periodontal treatment In teeth with root canal filling: Endodontic retreatment, apexification or tooth extraction depending on the prognosis Avital pulp with symptoms without periapical radiolucency on radiographs Endodontic treatment or tooth extraction (which might be necessary in case of pre-radiotherapy time limitations) Endodontic treatment or tooth extraction depending on the prognosis Avital pulp without symptoms and without periapical radiolucency on radiographs Endodontic treatment or tooth extraction (needed in case of pre-radiotherapy time limitations) Endodontic treatment (which can be postponed until after radiotherapy) Periodontal disease with: Pockets 4–5 mm Initial periodontal therapy Initial periodontal therapy Pockets ≥6 mm Tooth extraction Initial periodontal therapy Gingival recessions ≥ 6 mm Tooth extraction Only recession requires no treatment Furcation ≥ grade 1 Tooth extraction Initial periodontal therapy Mobility ≥ grade 1 Tooth extraction Initial periodontal therapy Impacted teeth or roots fully covered by bone without radiographic abnormalities No treatment If problems are expected in the future: tooth extraction No treatment Impacted teeth or roots not fully covered by bone or with radiographic abnormalities (eg, cysts, apical radiolucency) Tooth extraction No treatment or, in case of symptoms, surgical removal Roots with periapical radiolucency might be worth preserving by endodontic treatment and restoration (which can be postponed until after radiotherapy) Cysts Surgical removal Surgical removal Internal or external root resorption Tooth extraction Endodontic treatment or tooth extraction depending on the prognosis Open in new tab Table 1. Treatment of oral foci of infection within or outside the radiation field Assessed tooth problems . Cumulative dose > 40Gy . Cumulative dose < 40 Gy or outside the radiation portal . Caries profunda Tooth extraction Restoration, if necessary combined with endodontic treatment, or tooth extraction Periapical pathosis (on radiographs) without symptoms and/or additional problems In teeth without root canal filling: In teeth without root canal filling: Endodontic treatment and/or apexification Endodontic treatment In teeth with root canal filling: In teeth with root canal filling: Endodontic re-treatment, apexification, or tooth extraction (needed in case of pre-radiotherapy time limitations) Endodontic retreatment, apexification, or tooth extraction Treatment can be postponed until after radiotherapy Extensive periapical pathosis (on radiographs) combined with periodontal disease, in afunctional teeth or with symptoms Tooth extraction In teeth without root canal filling: Endodontic treatment combined with initial periodontal treatment In teeth with root canal filling: Endodontic retreatment, apexification or tooth extraction depending on the prognosis Avital pulp with symptoms without periapical radiolucency on radiographs Endodontic treatment or tooth extraction (which might be necessary in case of pre-radiotherapy time limitations) Endodontic treatment or tooth extraction depending on the prognosis Avital pulp without symptoms and without periapical radiolucency on radiographs Endodontic treatment or tooth extraction (needed in case of pre-radiotherapy time limitations) Endodontic treatment (which can be postponed until after radiotherapy) Periodontal disease with: Pockets 4–5 mm Initial periodontal therapy Initial periodontal therapy Pockets ≥6 mm Tooth extraction Initial periodontal therapy Gingival recessions ≥ 6 mm Tooth extraction Only recession requires no treatment Furcation ≥ grade 1 Tooth extraction Initial periodontal therapy Mobility ≥ grade 1 Tooth extraction Initial periodontal therapy Impacted teeth or roots fully covered by bone without radiographic abnormalities No treatment If problems are expected in the future: tooth extraction No treatment Impacted teeth or roots not fully covered by bone or with radiographic abnormalities (eg, cysts, apical radiolucency) Tooth extraction No treatment or, in case of symptoms, surgical removal Roots with periapical radiolucency might be worth preserving by endodontic treatment and restoration (which can be postponed until after radiotherapy) Cysts Surgical removal Surgical removal Internal or external root resorption Tooth extraction Endodontic treatment or tooth extraction depending on the prognosis Assessed tooth problems . Cumulative dose > 40Gy . Cumulative dose < 40 Gy or outside the radiation portal . Caries profunda Tooth extraction Restoration, if necessary combined with endodontic treatment, or tooth extraction Periapical pathosis (on radiographs) without symptoms and/or additional problems In teeth without root canal filling: In teeth without root canal filling: Endodontic treatment and/or apexification Endodontic treatment In teeth with root canal filling: In teeth with root canal filling: Endodontic re-treatment, apexification, or tooth extraction (needed in case of pre-radiotherapy time limitations) Endodontic retreatment, apexification, or tooth extraction Treatment can be postponed until after radiotherapy Extensive periapical pathosis (on radiographs) combined with periodontal disease, in afunctional teeth or with symptoms Tooth extraction In teeth without root canal filling: Endodontic treatment combined with initial periodontal treatment In teeth with root canal filling: Endodontic retreatment, apexification or tooth extraction depending on the prognosis Avital pulp with symptoms without periapical radiolucency on radiographs Endodontic treatment or tooth extraction (which might be necessary in case of pre-radiotherapy time limitations) Endodontic treatment or tooth extraction depending on the prognosis Avital pulp without symptoms and without periapical radiolucency on radiographs Endodontic treatment or tooth extraction (needed in case of pre-radiotherapy time limitations) Endodontic treatment (which can be postponed until after radiotherapy) Periodontal disease with: Pockets 4–5 mm Initial periodontal therapy Initial periodontal therapy Pockets ≥6 mm Tooth extraction Initial periodontal therapy Gingival recessions ≥ 6 mm Tooth extraction Only recession requires no treatment Furcation ≥ grade 1 Tooth extraction Initial periodontal therapy Mobility ≥ grade 1 Tooth extraction Initial periodontal therapy Impacted teeth or roots fully covered by bone without radiographic abnormalities No treatment If problems are expected in the future: tooth extraction No treatment Impacted teeth or roots not fully covered by bone or with radiographic abnormalities (eg, cysts, apical radiolucency) Tooth extraction No treatment or, in case of symptoms, surgical removal Roots with periapical radiolucency might be worth preserving by endodontic treatment and restoration (which can be postponed until after radiotherapy) Cysts Surgical removal Surgical removal Internal or external root resorption Tooth extraction Endodontic treatment or tooth extraction depending on the prognosis Open in new tab Extractions should be performed as atraumatically as possible, with primary closure whenever possible (50,52). It has been recently shown in an animal model that extraction of molars increased the impact of the cellular effects of radiation (59). Healing intervals that are frequently cited to reduce risk for ORN development range from 10 to 14 days (29,30,40,50,52,60). An interval of 14 days can still, however, pose a minor risk for the development of ORN. According to Marx and Johnson (9), risk for ORN development can be reduced to nearly zero when a 21-day or greater interval between extraction and initiation of radiation therapy is considered. From a recent systematic review, no conclusions could be drawn about a definition of an oral focus of infection and whether pre-radiation elimination of these foci is indeed mandatory (58). However, until it is known from prospective trials whether pre-radiation elimination of dental foci of infection is indeed feasible to reduce the risk on developing ORN, it is advised to continue with removal of dental foci of infection before onset of radiotherapy (Table 1). The latter agrees with the observation by Schuurhuis et al. (49,56) that a worse periodontal condition at dental screening and initial periodontal therapy to safeguard these teeth are a major risk factor of developing ORN. Thus, as mentioned before, it is generally accepted that all teeth with a questionable prognosis must be extracted before radiotherapy (Table 1) (38,50,52,55–58). Moreover, the less motivated the patient for dental care and hygiene, the more aggressive one should be in extracting teeth prior to radiotherapy (29,30,50,54,61,62). The classic literature strongly suggests the use of HBO as an adjuvant therapy when (dentoalveolar) surgery is needed after radiotherapy, particularly if the mandible or maxilla has received a cumulative dose greater than 65 Gy (45,63). Marx et al. (64) provide some support for this assumption as they reported an ORN incidence of 5% in HBO-treated patients needing surgery when compared with 30% in patients treated with conventional antibiotic prophylaxis in preventing ORN. HBO therapy stimulates angiogenesis with increased neovascularization and optimization of cellular levels of oxygen for osteoblast and fibroblast proliferation, collagen formation, and support of ingrowing blood vessels, thereby enhancing the healing potential in irradiated compromised tissues (65). Recently it was also shown that HBO accelerates osteoblast differentiation and promotes bone formation (66). If extensive wounding or extraction in radiation portals is necessary, then HBO treatment should be used both before surgery and after wounding (65). A multicenter study by Annane and colleagues (35) demonstrated no statistically significant improvement with HBO compared to room air in the treatment of ORN; however, the study was stopped for potentially worse outcomes in the HBO arm with only 68 patients included totally. Furthermore, applying HBO did not reduce the (low) risk of developing ORN after dental implant placement in irradiated jawbone (67). This provides clinical evidence that the Marx model of ORN and treatment with HBO cannot be reproduced clinically. The latter is also in line with the conclusion from the latest review by the Cochrane Collaboration showing that HBO treatment might be of some benefit in preventing the development of ORN following tooth extraction in an irradiated field (63), but that HBO treatment in irradiated patients requiring dental implants seemed to not offer any appreciable clinical effects (68). Furthermore, there is a 5- to 6-month window of tissue repair and healing before the onset of progressive fibrosis and loss of vascularity (9). This healing phase is a much safer phase during which to conduct necessary extractions, and HBO is usually not needed. New trials on the efficacy of HBO therapy have started but no data are available yet (69). Management of ORN If ORN develops, the management remains difficult and can be prolonged unsuccessfully. This is due to lack of suitable proven treatment methods and the biological background of the radiation injury to the jawbone. Conservative management eventually combined with surgical therapies are the common treatment options, but a conservative approach should be limited to early-onset ORN, whereas radical surgery is indicated for an advanced or refractory lesion (70). Besides traditional methods such as HBO to improve vascularity of the tissues, a number of pharmacological modalities to treat ORN have become within reach (27). Thus, there are two goals in the treatment of ORN: elimination of the necrotic bone and improvement in the vascularity of the remaining radiation-damage tissues (7). The first step is debridement of all bone that is no longer vascularized. Removal of this dead bone eliminates any niche for continued infection and inflammation but does nothing to improve the vascularity of the adjacent tissue bed and the remaining vascularised bone. This management includes antibiotic treatment with local curettage and debridement combined with small sequestrotomy. Local surgical management is conducted under local anaesthesia. More extensive surgical therapies include extensive sequestrotomy to remove all the dead bone combined with marginal of complete resection of affected parts of the mandible. These types of interventions often need to be combined with soft tissue reconstruction. Rarely free flaps are indicated for reconstruction (71), but when such flaps are needed free tissue transfer can apparently be used without need of HBO treatment (70). Strict indications for the different types of therapies are not clearly defined, however. The cure rate of limited ORN by conservative therapy is shown to be approximately 50%, whereas the cure rate of surgical approaches when conservative therapy has failed is approximately 40% (72). Next, because issues remain compromised by the previous radiation and are at continued risk for the development of ORN in the future, a protocol has been developed aimed not only to improve the healing of radiation-injured tissue but also permanently increase their vascularity. In this so-called Marx protocol antibiotic therapy, HBO therapy and debridement are combined (7,47). Bone exposures of the mandible are initially treated by local debridement and HBO therapy (stage I treatment). Smaller defects frequently close with this management. Defects that do not fully respond are treated by marginal mandibulectomy of the involved region and more HBO (stage II). Failure of stage II management, initial defects that involve the inferior border of the mandible, defects having an oro-cutaneous fistula, or pathologic fractures are managed by resection of the involved portion of the mandible to a margin of healthy bone and stabilization of the continuity defect (stage III). It has been suggested that a resection should include not just the affected bone but should be extended to obtain viable bone at the resection margin (Figures 4 and 5) (67). Where exactly the viable bone is situated is difficult to ascertain (73,74). A new approach could be to integrate the field of high radiation dose into the surgical plan. Such an approach is possible with 3D technology that uses the radiotherapy planning Digital Imaging and Communications in Medicine (Figures 4 and 5). Because ORN is a disease of hypovascularity and not necessarily an infection, antibiotic therapy is considered adjunctive. The mainstay of treatment is surgical, and in fact HBO is also an adjuvant and its clinical usefulness remains controversial (35,70). As also mentioned before in the prevention section, from a recent review by the Cochrane Collaboration group it was concluded that some evidence exists that HBO therapy improves the healing as adjuvant therapy in the treatment of ORN after hemi-mandibulectomy and reconstruction, and it prevents the development of ORN following tooth extraction from an earlier radiated jaw part (63). Figure 4. Open in new tabDownload slide Planning osteoradionecrosis (ORN) (3-dimensional [3D] planning). 3D visualization of radiation field for planning of resection of ORN of mandibular bone in a patient previously surgically treated for a T4N2c squamous cell carcinoma of the floor of mouth with a marginal mandible resection and bilateral neck dissection and post-operative radiotherapy to a maximum dose of 56 Gy. A) Visualization of the mandible with a pathological fracture due to ORN. B) Visualization of the 56 Gy planned target volume (PTV), in this case the highest radiation dose. C) Cutting planes planned just dorsal to the 56Gy PTV. D) 3D virtual planning of reconstruction with the patients’ fibula bone of the virtual resected mandible. Figure 4. Open in new tabDownload slide Planning osteoradionecrosis (ORN) (3-dimensional [3D] planning). 3D visualization of radiation field for planning of resection of ORN of mandibular bone in a patient previously surgically treated for a T4N2c squamous cell carcinoma of the floor of mouth with a marginal mandible resection and bilateral neck dissection and post-operative radiotherapy to a maximum dose of 56 Gy. A) Visualization of the mandible with a pathological fracture due to ORN. B) Visualization of the 56 Gy planned target volume (PTV), in this case the highest radiation dose. C) Cutting planes planned just dorsal to the 56Gy PTV. D) 3D virtual planning of reconstruction with the patients’ fibula bone of the virtual resected mandible. Figure 5. Open in new tabDownload slide Surgical treatment of osteoradionecrosis (ORN) after 3-dimensional virtual planning. Clinical pictures of the same patient as shown in Figure 4.A) Intra-oral view of the ORN of the mandible. B) Surgical exposure of pathological fracture of mandible. C) After resection of necrotic bone of the mandible using cutting guides based on the virtual planning as shown in Figure 4. D) View after placement of fibula in defect of mandible. Figure 5. Open in new tabDownload slide Surgical treatment of osteoradionecrosis (ORN) after 3-dimensional virtual planning. Clinical pictures of the same patient as shown in Figure 4.A) Intra-oral view of the ORN of the mandible. B) Surgical exposure of pathological fracture of mandible. C) After resection of necrotic bone of the mandible using cutting guides based on the virtual planning as shown in Figure 4. D) View after placement of fibula in defect of mandible. Pharmacological management is an additional therapeutic strategy for ORN, such as pentoxifylline, tocopherol, and clodronate (27,75). Pentoxifylline is used to dilate vessels and increase erythrocyte flexibility, both factors to enhance blood flow, as well as to reduce proliferation of dermal fibroblasts and to promote collagenase activity. Tocopherol (vitamin E) is a weak antioxidant able to act as a radical scavenger and also has an antifibrotic activity. Clodronate is a bisphosphonate that reduces osteoclasts numbers and activity and has an anti-inflammatory activity by reducing the levels of interleukin (IL)-1β, IL-6, and tumor necrosis factorα. The combination of these drugs has been shown to promote healing of ORN (Figure 6) (27,75,76). This approach is promising, but its efficacy has to be confirmed by other groups. Figure 6. Open in new tabDownload slide Pharmacological treatment of osteoradionecrosis (ORN) with Pentoclo protocol. A) Patient with ORN after surgical treatment of a T2N2b squamous cell carcinoma followed by postoperative radiotherapy to a maximum of 66 Gy. The ORNs did not respond to surgical debridement with pre and postoperative HBO. B) The patient was treated according to the pentoclo protocol. The pentoxifylline-tocopherol combination decreases the superficial fibrosis induced by radiotherapy. Potentiation by clodronate (PENTOCLO) appears to be effective in ORN of the mandible (70). The ORN responded to this therapy after a treatment period of 11 months. On two occasions softened necrotic bone was removed after spontaneous sequestration. Figure 6. Open in new tabDownload slide Pharmacological treatment of osteoradionecrosis (ORN) with Pentoclo protocol. A) Patient with ORN after surgical treatment of a T2N2b squamous cell carcinoma followed by postoperative radiotherapy to a maximum of 66 Gy. The ORNs did not respond to surgical debridement with pre and postoperative HBO. B) The patient was treated according to the pentoclo protocol. The pentoxifylline-tocopherol combination decreases the superficial fibrosis induced by radiotherapy. Potentiation by clodronate (PENTOCLO) appears to be effective in ORN of the mandible (70). The ORN responded to this therapy after a treatment period of 11 months. On two occasions softened necrotic bone was removed after spontaneous sequestration. Strategies to Promote Development and Funding for the New Research Since the 1989 NIH Development Consensus Conference on the Oral Complications of Cancer Therapies, significant progress has been made in the ability to reduce bone damage due to advances in radiation techniques, including optimizing of 3D treatment planning and IMRT. Currently, IMRT and its next step, proton therapy, have the greatest potential as a management strategy for prevention of jawbone damage in head and neck cancer patients. Nonetheless, many of these therapies still only offer partial reduction of the permanent injuries of healthy jaw bones. Other studies aim to prevent bone damage or to improve bone healing after radiation injury. Such studies will include improving surgical insight and operation techniques based on merging radiation field data with imaging data of damaged bone and 3D virtual planning data of the surgery to be performed. Such research efforts are very costly and need the involvement of researchers that have access to national and international scientific societies (eg, European Organisation for Research and Treatment of Cancer Head & Neck Cancer Group, European Society for Therapeutic Radiation Oncology, International Society for Stem Cell Research, Stem Cells in Development and Disease, and Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology). The same applies for randomized clinical trials assessing the potential benefit of HBO and pharmacologic management. Researchers performing such studies need to have access to a network that allows them to successfully compete for multinational translational grants from, for example, the National Institutes of Health and the European Framework Programs as well as to have access to sufficient large cohorts of well-defined patients with ORN or being at high risk of developing ORN. Only this way can sound, well-designed trials be performed, probably, because of the needed patient numbers, in a multicenter context. Fortunately, interest in growing in governmental, public, and private funding organizations as well as among researchers researching healthy aging, which increases the opportunities of getting such studies funded. This is also favorable because research aimed at prevention and reduction of the morbidity of cancer treatment fits well within the National Institutes of Health and European Framework programs. Funding Unrestricted educational grant support for the writing of this report was made available from the University Medical Center Groningen. Notes Affiliations of authors: Department of Oral & Maxillofacial Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (FKLS, MJHW, AV); Department of Oral Medicine, Carolinas Medical Center, Charlotte, NC (MTB); Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, Neag Comprehensive Cancer Center, UConn Health, Farmington, CT (DEP). F. Spijkervet has no conflicts of interest to declare. M. Brennan is a consultant for AFYX and Medimmune; none of this consulting activity is related to the content of this manuscript. D. Peterson has received consulting fees from Amgen Inc., Optum Epidemiology, PSI CRO, SAI MedPartner LLC, and AEC Partners. He also receives consulting fees from and holds equity ownership in Applied Glycan Technologies, Inc. None of this consulting activity is related to the content of this manuscript. M. Witjes has no conflicts of interest to declare. A. Vissink has no conflicts of interest to declare. For support see Funding Acknowledgement section of Monograph. References 1 Barton MB , Jacob S, Shafiq J, et al. . Estimating the demand for radiotherapy from the evidence: a review of changes from 2003 to 2012 . Radiother Oncol . 2014 ; 112 1 : 140 – 144 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Delaney GP , Barton MB. Evidence-based estimates of the demand for radiotherapy . Clin Oncol. 2015 ; 27 2 : 70 – 76 . Google Scholar Crossref Search ADS WorldCat 3 Grégoire V , Langendijk JA, Nuyts S. Advances in radiotherapy for head and neck cancer . 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Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com © The Author(s) 2019. Published by Oxford University Press. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI Monographs Oxford University Press

Research Frontiers in Oral Toxicities of Cancer Therapies: Osteoradionecrosis of the Jaws

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Abstract

Abstract The deleterious effects of head and neck radiation on bone, with osteoradionecrosis (ORN) as the major disabling side effect of head and neck cancer treatment, are difficult to prevent and hard to treat. This review focuses on the current state of the science regarding the pathobiology, clinical impact, and management of ORN. With regard to the pathobiology underlying ORN, it is not yet confirmed whether the current radiation schedules by 3-dimensional conformal radiotherapy and intensity modified radiotherapy result in an unchanged, decreased, or increased risk of developing ORN when compared with conventional radiation treatment, the main risk factor being the total radiation dose delivered on any clinically significant surface of the mandible. With regard to the prevention of ORN, a thorough, early pre-irradiation dental assessment is still considered the first step to reduce the hazard of developing ORN post-radiotherapy, and hyperbaric oxygen (HBO) treatment reduces the risk of developing ORN in case of dental surgery in an irradiated field. With regard to the treatment of ORN, the focus is bidirectional: elimination of the necrotic bone and improving the vascularity of the normal tissues that were included in the radiation portal. The cure rate of limited ORN by conservative therapy is approximately 50%, and the cure rate of surgical approaches when conservative therapy has failed is approximately 40%. Whether it is effective to support conservative or surgical treatment with HBO as an adjuvant is not set. HBO treatment is shown to increase the vascularity of hard and soft tissues and has been reported to be beneficial in selected cases. However, in randomized clinical trials comparing the preventive effect of HBO on developing ORN with, eg, antibiotic coverage in patients needing dental surgery, the preventive effect of HBO was not shown to surpass that of a more conservative approach. More recently, pharmacologic management was introduced in the treatment of ORN with success, but its efficacy has to be confirmed in randomized clinical trials. The major problem of performing well-designed randomized clinical trials in ORN is having access to large numbers of patients with well-defined, comparable cases of ORN. Because many institutions will not have large numbers of such ORN cases, national and international scientific societies must be approached to join multicenter trials. Fortunately, the interest of funding organizations and the number researchers with an interest in healthy aging is growing. Research aimed at prevention and reduction of the morbidity of cancer treatment fits well within these programs. Approximately 75% of patients with head and neck cancer need radiotherapy as a primary treatment, as an adjunct to surgery, in combination with chemotherapy or as palliation (1–3). Of these patients, 50% will be long-term survivors for whom a low level of treatment morbidity is of major importance. Clinically significant nonosseous late effects of head and neck radiation are well documented in the literature and include xerostomia, compromised swallowing and speech, and increased risk for developing dental caries and oral infections (4,5). These toxicities can collectively have a negative impact on patients’ quality of life. Of note, however, is that the deleterious effects of head and neck radiation on bone are among the hardest to treat and most disabling side-effects of head and neck cancer treatment (6). When osteoradionecrosis (ORN) of the maxilla or mandible occurs, progression of ORN can be difficult to control, and resultant large osseous defects may develop (Figure 1). Figure 1. Open in new tabDownload slide Osteoradionecrosis of the mandible in an edentulous patient treated for a T3N2b squamous cell carcinoma of the floor of the mouth, 1 year after ablative surgery and intensity modified radiotherapy. Figure 1. Open in new tabDownload slide Osteoradionecrosis of the mandible in an edentulous patient treated for a T3N2b squamous cell carcinoma of the floor of the mouth, 1 year after ablative surgery and intensity modified radiotherapy. ORN is defined as bone death secondary to radiotherapy and is characterized by a nonhealing area of exposed bone (7–9). A wide range of clinical presentations and symptoms is associated with ORN, from asymptomatic exposed bone to more advanced stages of ORN that frequently present with severe pain and infection of the bone requiring surgical resection and reconstruction for management (Figure 2) (6,10). Moreover, it is not yet confirmed whether the replacement of the more conventional radiation schedules by 3D conformal radiotherapy and intensity modified radiotherapy (IMRT) result in an unchanged, decreased, or increased risk of developing ORN. The main risk factor for developing ORN is the cumulative radiation dose received by any clinically significant volume of the mandible. Figure 2. Open in new tabDownload slide Severe osteoradionecrosis after treatment of a T4N2b squamous cell carcinoma of the gingiva and floor of mouth with ablative and reconstructive surgery with a free vascularized transplant and postoperative intensity modified radiotherapy. Figure 2. Open in new tabDownload slide Severe osteoradionecrosis after treatment of a T4N2b squamous cell carcinoma of the gingiva and floor of mouth with ablative and reconstructive surgery with a free vascularized transplant and postoperative intensity modified radiotherapy. Pathobiological mechanisms underlying late radiation injuries of the jawbone have not yet been fully established. Presumably, late damage to bone and its supportive tissues is characterized by a density reduction of small blood vessels and replacement of normal tissue cells with fibrous tissue (5,11–15). Due to the resulting insufficient oxygen supply to sustain normal function, this progressive and delayed radiation damage may reach a critical point where the tissue breaks down to form an area of cell death (soft tissue necrosis with or without ORN). This review focuses on the current state of the science regarding the pathobiology, clinical impact, and management of ORN. New research directions for the field are indicated, based on current gaps in mechanism as well as new treatment strategies. The following key research questions will be addressed in the next paragraphs: What is the mechanism underlying development of ORN of the jaws? Among others, does ORN result from radiation injury to the bone modeling system and/or to the vascular system, or is it the result of fibro-apoptotic bone changes? Has the risk on developing ORN of the jaws been changed by the introduction of IMRT and/or concurrent chemotherapy in the radiation treatment of head and neck tumors? And what about even newer radiation techniques, eg, protons that allow for a superior dose distribution due to a more targeted location of the maximum deposited energy dose? Can development of ORN of the jaws be prevented? Among others, is there any evidence that pretreatment oral examination followed by removal of oral foci of infection is prophylactic, and is there a need for hyperbaric oxygen (HBO) and/or antibiotics when needing oral surgery in irradiated jaws? How should ORN of the jaws be managed when it has developed? In other words, when should it be addressed conventionally and when is there a need for antibiotics, surgery, and/or HBO? And what about pharmacologic management of ORN? Pathobiology: Current Paradigm and New Frontiers Head and Neck Radiation The goal in radiotherapy is to maximize the biological effect of radiation on the tumor while limiting its toxic effects on normal tissues. Tolerance of the adjacent normal tissues is the most important dose-limiting factor in radiotherapy. Therefore, treatment is administered over several sessions to give the normal tissue time to recover because normal tissue has better damage-repair capabilities than tumor cells (16). Depending on stage and location of the primary tumor and (potentially) affected lymph nodes, the oral cavity, salivary glands, and jawbones of most head and neck cancer patients are at least to some extent located in the radiation portals. Thus, even with the most optimal fractionation schedule and radiation techniques, unwanted radiation-induced changes will occur in these tissues (3,5,11,12,17,18). The indicated cumulative radiation dose is based on location and type of malignancy and whether radiotherapy will be given alone or in combination with other modalities. Most patients with head and neck cancers, treated with a curative intent, receive a cumulative dose between 46 and 70 Gy. This dose is usually administered during a 5- to 7-week period, once a day, five to six times a week with 2 Gy per fraction (3,13,16). Several strategies to further increase locoregional tumor control without increasing the normal tissue complication probability has been developed and tested in clinical trials or are already implemented in daily clinical practice, including among others a 10% dose escalation with dose redistribution to increase tumor control probability. Currently, IMRT, either with or without concomitant chemotherapy, is most applied (3). In IMRT, computer-controlled photon accelerators distribute precise radiation doses to the tumor. The applied radiation dose is consistent with the 3-dimensional (3D) shape of the tumor by controlling, or modulating, the radiation beam’s intensity. The aim of this approach is to elevate the cumulative radiation dose near the gross tumor volume while decreasing the radiation to neighboring normal tissues to a minimum. Compared with conventional radiation therapy and 3D conformal radiotherapy, critical normal tissues can be spared to a greater extent (19–21). Comparison of the incidence of ORN after IMRT or conventional radiotherapy shows statistically significant differences (22). It has been suggested that higher mandibular radiotherapy dose volumes are related to higher incidence of ORN (23). Lower dose volumes in the mandible could be obtained by IMRT with the tumor adequately treated. Proton therapy generates an even more exquisite dose distribution in some patients, thus potentially further improving patient outcomes (3). IMRT and proton therapy are also thought to reduce long-term morbidity, especially damage to the salivary glands and ORN. Radiation and Bone The classic modeling for ORN published by Marx (24) includes the concept that radiation to the jaw leads to long-term biological changes including vasculature impairment, hypoxia, and impaired wound recovery and secondary infection. Alterations in bone matrix after irradiation develop relatively slowly, whereas it is thought that the initial changes in bone result from injury to the remodelling system (osteocytes, osteoblasts, and osteoclasts) and alterations of the vascular system become apparent later (25,26). Another hypothesis cites fibroapoptotic bone changes (12). In that hypothesis, bone and soft tissue damage is thought to result from radiation-induced fibrosis; acute radiation-induced inflammation with endothelial changes is followed by abnormal fibroblast activity with extra-cellular matrix disruption and finally late fibroatrophy. When fibroatrophy occurs, healed tissues are fragile and undergo late reactivation of the acute inflammatory response after injury (12,27). In addition to the effects on fibroblasts, osteoblasts tend to be more radiosensitive than osteoclasts; a relative increase in the lytic activity may thus occur. Whether the altered bone remodelling activity is the result of direct irradiation injury to the cells of the remodelling system, the indirect result of irradiation-induced vascular injury, or a combination of both phenomena is still a matter of debate. Is it involvement of osteoblasts, involvement of fibroblasts, or a combination of both? Radiation injury to the fine vasculature of bone and its surrounding tissues first leads to hyperaemia, followed by endarteritis, thrombosis, and a progressive occlusion and obliteration of small vessels. Within bone this results in further reduction of cell number and progressive fibrosis. With time the marrow exhibits marked acellularity and hypo- or avascularity, with significant fibrosis and fatty degeneration. Some lacunae may become devoid of osteocytes. The endosteum atrophies with clinically significant loss of active osteoblasts and osteoclasts. The periosteum demonstrates significant fibrosis, with a similar loss of remodelling elements (7,9,25,26,28–31). In 2012, Marx and Turson (13) reported that necrotic bone was present in all studied ORN specimens as evidenced by empty osteocytic lacunae, absence of osteoblastic rimming, and empty Haversian systems and Volkmann canals. Moreover, there was a notable absence of inflammatory cells and normal marrow elements or fat cells throughout the marrow. Bone marrow primarily consisted of acellular collagen, with only a rare cell nuclei noted. Of a greater clinical impact is their observation of an absence of functioning blood vessels in all studied specimens. Remnants of old blood vessels were observed as devoid of endothelial and adventitial cells, leaving only a ring of basal lamina. Microorganisms were present in about one-half of the studied specimen on the surface of the bone. Periosteum was also preserved in about one-half of the studied specimens, but that periosteum was seen to be acellular and avascular. Thus, the histopathological evidence reported by Marx and Turson (13) supports a physical injury to bone and the soft tissues covering bone from the high linear energy transfer of radiotherapy underlying the development of ORN. In contrast to bisphosphonate osteonecrosis, in ORN no osteoclastic impairment underlies the development of ORN, but ORN is the result of direct injury to all cell populations in the field of radiation. Unlike in bisphosphonate osteonecrosis, radiation has directly damaged the blood supply, the periosteum, and the overlying mucosa (Figure 3) (32). Figure 3. Open in new tabDownload slide Current insights in pathobiological process of osteoradionecrosis [modified from Lyons et al. (32)]. Figure 3. Open in new tabDownload slide Current insights in pathobiological process of osteoradionecrosis [modified from Lyons et al. (32)]. In a prospective imaging trial, the effect of radiotherapy on bone perfusion was demonstrated with a dynamic contrast-enhanced MRI. With this technique, dose-dependent alterations in mandibular bone vascularity during chemoradiotherapy could be observed (33). The studied biomarkers were physiological correlates of acute mandibular vascular injury and recovery temporal kinetics. Further validation of these parameters for prediction and detection of late radiotherapy mandibular sequelae is warranted. Prevalence of ORN In a systematic review by Peterson et al. (34), the prevalence of ORN was assessed by type of radiation therapy. Taking into account quality measures of published studies, the weighted prevalence of ORN was found to be 7.3% (95% confidence interval [CI] = 4.8% to 10%) for conventional radiotherapy, but there is a great variety between the studies reporting prevalence rates with prevalence up to 25.5% (7,14,35–38). The incidence of osteonecrosis of the maxilla is much lower than in the mandible (38–40). Moreover, it has been reported that the prevalence of ORN is less with IMRT at 5.2% (95% CI = 0.0% to 12.0%) (34). However, there are also recent indications that the risk might increase as treatment of head and neck cancer with IMRT might result in unwanted radiation exposure to the whole mandible bone (41) and ORN rates were shown to be rather high when IMRT was combined with bone resection (20). Particularly, mandibular molar regions for base of tongue, tonsil, and hypopharynx cancers were shown to receive higher IMRT doses on average, posing the greatest ORN risk (42). Finally, a recent study in a large cohort of patients revealed that the time frame to develop jaw complications after IMRT apparently has a longer latency, but with time the risk of developing ORN (25.5% after median follow-up of 3.4 years) is similar to that of non-IMRT treatment (25%, 1.2 years; in that study, 25.5% after a median follow-up of 3.4 years) (37). ORN following dental extractions post-radiotherapy occurs in upward of 50% of cases (43); therefore, pre-radiation oral evaluation and dental management of potential odontogenic or periodontal infections is vital. Spontaneous ORN, which has been reported to occur in almost 35% of all cases of ORN, is related to increased age, higher body mass index, use of steroids, smoking, high radiation dose (>65 Gy), field of radiation (volume of the mandible included in the field and proximity of maximal dosing to bone), hyperfractionation, use of radiation implant sources too close to the bone, and combined interstitial and external beam irradiation (7,9,24,37–40,44–48). The spontaneous form of ORN represents a greater outright cellular kill of normal tissue elements and an inability of soft and hard tissue to keep up with cellular turnover and collagen synthesis. This type of necrosis usually occurs within the first 2 years after radiotherapy (6,9,19,24,38,47), but it can occur at any time later after irradiation (8,36,38). Clinical Management: Successes and Barriers Prevention of ORN Besides improved radiotherapeutic modalities and shielding, the first step toward prevention of ORN has been presumed to be a thorough, early pre-irradiation dental assessment (Table 1) (49). This pretreatment oral examination should attempt to identify the main factors that will increase the risk for ORN. On the basis of this inventory, steps may be taken to control or eliminate as many factors as is practical before radiotherapy begins (7,14,38,45,49–57). The primary goal should be to optimize the condition of the patient’s dentition to confirm that high-risk procedures (extraction or surgical removal of teeth, apicoectomies) will not have to be performed in the post-irradiation period (28–30,38–40,45,50–53,57,58). To maximize the impact of screening, adequate time for treatment and healing must be allowed (51,52). Screening is of limited value if the inventory of oral foci of infection is performed too close to the start of radiation therapy, which will preclude dental intervention. Pre-irradiation extraction followed by inadequate healing time is known to predispose to ORN (7,9,37,40,58). Table 1. Treatment of oral foci of infection within or outside the radiation field Assessed tooth problems . Cumulative dose > 40Gy . Cumulative dose < 40 Gy or outside the radiation portal . Caries profunda Tooth extraction Restoration, if necessary combined with endodontic treatment, or tooth extraction Periapical pathosis (on radiographs) without symptoms and/or additional problems In teeth without root canal filling: In teeth without root canal filling: Endodontic treatment and/or apexification Endodontic treatment In teeth with root canal filling: In teeth with root canal filling: Endodontic re-treatment, apexification, or tooth extraction (needed in case of pre-radiotherapy time limitations) Endodontic retreatment, apexification, or tooth extraction Treatment can be postponed until after radiotherapy Extensive periapical pathosis (on radiographs) combined with periodontal disease, in afunctional teeth or with symptoms Tooth extraction In teeth without root canal filling: Endodontic treatment combined with initial periodontal treatment In teeth with root canal filling: Endodontic retreatment, apexification or tooth extraction depending on the prognosis Avital pulp with symptoms without periapical radiolucency on radiographs Endodontic treatment or tooth extraction (which might be necessary in case of pre-radiotherapy time limitations) Endodontic treatment or tooth extraction depending on the prognosis Avital pulp without symptoms and without periapical radiolucency on radiographs Endodontic treatment or tooth extraction (needed in case of pre-radiotherapy time limitations) Endodontic treatment (which can be postponed until after radiotherapy) Periodontal disease with: Pockets 4–5 mm Initial periodontal therapy Initial periodontal therapy Pockets ≥6 mm Tooth extraction Initial periodontal therapy Gingival recessions ≥ 6 mm Tooth extraction Only recession requires no treatment Furcation ≥ grade 1 Tooth extraction Initial periodontal therapy Mobility ≥ grade 1 Tooth extraction Initial periodontal therapy Impacted teeth or roots fully covered by bone without radiographic abnormalities No treatment If problems are expected in the future: tooth extraction No treatment Impacted teeth or roots not fully covered by bone or with radiographic abnormalities (eg, cysts, apical radiolucency) Tooth extraction No treatment or, in case of symptoms, surgical removal Roots with periapical radiolucency might be worth preserving by endodontic treatment and restoration (which can be postponed until after radiotherapy) Cysts Surgical removal Surgical removal Internal or external root resorption Tooth extraction Endodontic treatment or tooth extraction depending on the prognosis Assessed tooth problems . Cumulative dose > 40Gy . Cumulative dose < 40 Gy or outside the radiation portal . Caries profunda Tooth extraction Restoration, if necessary combined with endodontic treatment, or tooth extraction Periapical pathosis (on radiographs) without symptoms and/or additional problems In teeth without root canal filling: In teeth without root canal filling: Endodontic treatment and/or apexification Endodontic treatment In teeth with root canal filling: In teeth with root canal filling: Endodontic re-treatment, apexification, or tooth extraction (needed in case of pre-radiotherapy time limitations) Endodontic retreatment, apexification, or tooth extraction Treatment can be postponed until after radiotherapy Extensive periapical pathosis (on radiographs) combined with periodontal disease, in afunctional teeth or with symptoms Tooth extraction In teeth without root canal filling: Endodontic treatment combined with initial periodontal treatment In teeth with root canal filling: Endodontic retreatment, apexification or tooth extraction depending on the prognosis Avital pulp with symptoms without periapical radiolucency on radiographs Endodontic treatment or tooth extraction (which might be necessary in case of pre-radiotherapy time limitations) Endodontic treatment or tooth extraction depending on the prognosis Avital pulp without symptoms and without periapical radiolucency on radiographs Endodontic treatment or tooth extraction (needed in case of pre-radiotherapy time limitations) Endodontic treatment (which can be postponed until after radiotherapy) Periodontal disease with: Pockets 4–5 mm Initial periodontal therapy Initial periodontal therapy Pockets ≥6 mm Tooth extraction Initial periodontal therapy Gingival recessions ≥ 6 mm Tooth extraction Only recession requires no treatment Furcation ≥ grade 1 Tooth extraction Initial periodontal therapy Mobility ≥ grade 1 Tooth extraction Initial periodontal therapy Impacted teeth or roots fully covered by bone without radiographic abnormalities No treatment If problems are expected in the future: tooth extraction No treatment Impacted teeth or roots not fully covered by bone or with radiographic abnormalities (eg, cysts, apical radiolucency) Tooth extraction No treatment or, in case of symptoms, surgical removal Roots with periapical radiolucency might be worth preserving by endodontic treatment and restoration (which can be postponed until after radiotherapy) Cysts Surgical removal Surgical removal Internal or external root resorption Tooth extraction Endodontic treatment or tooth extraction depending on the prognosis Open in new tab Table 1. Treatment of oral foci of infection within or outside the radiation field Assessed tooth problems . Cumulative dose > 40Gy . Cumulative dose < 40 Gy or outside the radiation portal . Caries profunda Tooth extraction Restoration, if necessary combined with endodontic treatment, or tooth extraction Periapical pathosis (on radiographs) without symptoms and/or additional problems In teeth without root canal filling: In teeth without root canal filling: Endodontic treatment and/or apexification Endodontic treatment In teeth with root canal filling: In teeth with root canal filling: Endodontic re-treatment, apexification, or tooth extraction (needed in case of pre-radiotherapy time limitations) Endodontic retreatment, apexification, or tooth extraction Treatment can be postponed until after radiotherapy Extensive periapical pathosis (on radiographs) combined with periodontal disease, in afunctional teeth or with symptoms Tooth extraction In teeth without root canal filling: Endodontic treatment combined with initial periodontal treatment In teeth with root canal filling: Endodontic retreatment, apexification or tooth extraction depending on the prognosis Avital pulp with symptoms without periapical radiolucency on radiographs Endodontic treatment or tooth extraction (which might be necessary in case of pre-radiotherapy time limitations) Endodontic treatment or tooth extraction depending on the prognosis Avital pulp without symptoms and without periapical radiolucency on radiographs Endodontic treatment or tooth extraction (needed in case of pre-radiotherapy time limitations) Endodontic treatment (which can be postponed until after radiotherapy) Periodontal disease with: Pockets 4–5 mm Initial periodontal therapy Initial periodontal therapy Pockets ≥6 mm Tooth extraction Initial periodontal therapy Gingival recessions ≥ 6 mm Tooth extraction Only recession requires no treatment Furcation ≥ grade 1 Tooth extraction Initial periodontal therapy Mobility ≥ grade 1 Tooth extraction Initial periodontal therapy Impacted teeth or roots fully covered by bone without radiographic abnormalities No treatment If problems are expected in the future: tooth extraction No treatment Impacted teeth or roots not fully covered by bone or with radiographic abnormalities (eg, cysts, apical radiolucency) Tooth extraction No treatment or, in case of symptoms, surgical removal Roots with periapical radiolucency might be worth preserving by endodontic treatment and restoration (which can be postponed until after radiotherapy) Cysts Surgical removal Surgical removal Internal or external root resorption Tooth extraction Endodontic treatment or tooth extraction depending on the prognosis Assessed tooth problems . Cumulative dose > 40Gy . Cumulative dose < 40 Gy or outside the radiation portal . Caries profunda Tooth extraction Restoration, if necessary combined with endodontic treatment, or tooth extraction Periapical pathosis (on radiographs) without symptoms and/or additional problems In teeth without root canal filling: In teeth without root canal filling: Endodontic treatment and/or apexification Endodontic treatment In teeth with root canal filling: In teeth with root canal filling: Endodontic re-treatment, apexification, or tooth extraction (needed in case of pre-radiotherapy time limitations) Endodontic retreatment, apexification, or tooth extraction Treatment can be postponed until after radiotherapy Extensive periapical pathosis (on radiographs) combined with periodontal disease, in afunctional teeth or with symptoms Tooth extraction In teeth without root canal filling: Endodontic treatment combined with initial periodontal treatment In teeth with root canal filling: Endodontic retreatment, apexification or tooth extraction depending on the prognosis Avital pulp with symptoms without periapical radiolucency on radiographs Endodontic treatment or tooth extraction (which might be necessary in case of pre-radiotherapy time limitations) Endodontic treatment or tooth extraction depending on the prognosis Avital pulp without symptoms and without periapical radiolucency on radiographs Endodontic treatment or tooth extraction (needed in case of pre-radiotherapy time limitations) Endodontic treatment (which can be postponed until after radiotherapy) Periodontal disease with: Pockets 4–5 mm Initial periodontal therapy Initial periodontal therapy Pockets ≥6 mm Tooth extraction Initial periodontal therapy Gingival recessions ≥ 6 mm Tooth extraction Only recession requires no treatment Furcation ≥ grade 1 Tooth extraction Initial periodontal therapy Mobility ≥ grade 1 Tooth extraction Initial periodontal therapy Impacted teeth or roots fully covered by bone without radiographic abnormalities No treatment If problems are expected in the future: tooth extraction No treatment Impacted teeth or roots not fully covered by bone or with radiographic abnormalities (eg, cysts, apical radiolucency) Tooth extraction No treatment or, in case of symptoms, surgical removal Roots with periapical radiolucency might be worth preserving by endodontic treatment and restoration (which can be postponed until after radiotherapy) Cysts Surgical removal Surgical removal Internal or external root resorption Tooth extraction Endodontic treatment or tooth extraction depending on the prognosis Open in new tab Extractions should be performed as atraumatically as possible, with primary closure whenever possible (50,52). It has been recently shown in an animal model that extraction of molars increased the impact of the cellular effects of radiation (59). Healing intervals that are frequently cited to reduce risk for ORN development range from 10 to 14 days (29,30,40,50,52,60). An interval of 14 days can still, however, pose a minor risk for the development of ORN. According to Marx and Johnson (9), risk for ORN development can be reduced to nearly zero when a 21-day or greater interval between extraction and initiation of radiation therapy is considered. From a recent systematic review, no conclusions could be drawn about a definition of an oral focus of infection and whether pre-radiation elimination of these foci is indeed mandatory (58). However, until it is known from prospective trials whether pre-radiation elimination of dental foci of infection is indeed feasible to reduce the risk on developing ORN, it is advised to continue with removal of dental foci of infection before onset of radiotherapy (Table 1). The latter agrees with the observation by Schuurhuis et al. (49,56) that a worse periodontal condition at dental screening and initial periodontal therapy to safeguard these teeth are a major risk factor of developing ORN. Thus, as mentioned before, it is generally accepted that all teeth with a questionable prognosis must be extracted before radiotherapy (Table 1) (38,50,52,55–58). Moreover, the less motivated the patient for dental care and hygiene, the more aggressive one should be in extracting teeth prior to radiotherapy (29,30,50,54,61,62). The classic literature strongly suggests the use of HBO as an adjuvant therapy when (dentoalveolar) surgery is needed after radiotherapy, particularly if the mandible or maxilla has received a cumulative dose greater than 65 Gy (45,63). Marx et al. (64) provide some support for this assumption as they reported an ORN incidence of 5% in HBO-treated patients needing surgery when compared with 30% in patients treated with conventional antibiotic prophylaxis in preventing ORN. HBO therapy stimulates angiogenesis with increased neovascularization and optimization of cellular levels of oxygen for osteoblast and fibroblast proliferation, collagen formation, and support of ingrowing blood vessels, thereby enhancing the healing potential in irradiated compromised tissues (65). Recently it was also shown that HBO accelerates osteoblast differentiation and promotes bone formation (66). If extensive wounding or extraction in radiation portals is necessary, then HBO treatment should be used both before surgery and after wounding (65). A multicenter study by Annane and colleagues (35) demonstrated no statistically significant improvement with HBO compared to room air in the treatment of ORN; however, the study was stopped for potentially worse outcomes in the HBO arm with only 68 patients included totally. Furthermore, applying HBO did not reduce the (low) risk of developing ORN after dental implant placement in irradiated jawbone (67). This provides clinical evidence that the Marx model of ORN and treatment with HBO cannot be reproduced clinically. The latter is also in line with the conclusion from the latest review by the Cochrane Collaboration showing that HBO treatment might be of some benefit in preventing the development of ORN following tooth extraction in an irradiated field (63), but that HBO treatment in irradiated patients requiring dental implants seemed to not offer any appreciable clinical effects (68). Furthermore, there is a 5- to 6-month window of tissue repair and healing before the onset of progressive fibrosis and loss of vascularity (9). This healing phase is a much safer phase during which to conduct necessary extractions, and HBO is usually not needed. New trials on the efficacy of HBO therapy have started but no data are available yet (69). Management of ORN If ORN develops, the management remains difficult and can be prolonged unsuccessfully. This is due to lack of suitable proven treatment methods and the biological background of the radiation injury to the jawbone. Conservative management eventually combined with surgical therapies are the common treatment options, but a conservative approach should be limited to early-onset ORN, whereas radical surgery is indicated for an advanced or refractory lesion (70). Besides traditional methods such as HBO to improve vascularity of the tissues, a number of pharmacological modalities to treat ORN have become within reach (27). Thus, there are two goals in the treatment of ORN: elimination of the necrotic bone and improvement in the vascularity of the remaining radiation-damage tissues (7). The first step is debridement of all bone that is no longer vascularized. Removal of this dead bone eliminates any niche for continued infection and inflammation but does nothing to improve the vascularity of the adjacent tissue bed and the remaining vascularised bone. This management includes antibiotic treatment with local curettage and debridement combined with small sequestrotomy. Local surgical management is conducted under local anaesthesia. More extensive surgical therapies include extensive sequestrotomy to remove all the dead bone combined with marginal of complete resection of affected parts of the mandible. These types of interventions often need to be combined with soft tissue reconstruction. Rarely free flaps are indicated for reconstruction (71), but when such flaps are needed free tissue transfer can apparently be used without need of HBO treatment (70). Strict indications for the different types of therapies are not clearly defined, however. The cure rate of limited ORN by conservative therapy is shown to be approximately 50%, whereas the cure rate of surgical approaches when conservative therapy has failed is approximately 40% (72). Next, because issues remain compromised by the previous radiation and are at continued risk for the development of ORN in the future, a protocol has been developed aimed not only to improve the healing of radiation-injured tissue but also permanently increase their vascularity. In this so-called Marx protocol antibiotic therapy, HBO therapy and debridement are combined (7,47). Bone exposures of the mandible are initially treated by local debridement and HBO therapy (stage I treatment). Smaller defects frequently close with this management. Defects that do not fully respond are treated by marginal mandibulectomy of the involved region and more HBO (stage II). Failure of stage II management, initial defects that involve the inferior border of the mandible, defects having an oro-cutaneous fistula, or pathologic fractures are managed by resection of the involved portion of the mandible to a margin of healthy bone and stabilization of the continuity defect (stage III). It has been suggested that a resection should include not just the affected bone but should be extended to obtain viable bone at the resection margin (Figures 4 and 5) (67). Where exactly the viable bone is situated is difficult to ascertain (73,74). A new approach could be to integrate the field of high radiation dose into the surgical plan. Such an approach is possible with 3D technology that uses the radiotherapy planning Digital Imaging and Communications in Medicine (Figures 4 and 5). Because ORN is a disease of hypovascularity and not necessarily an infection, antibiotic therapy is considered adjunctive. The mainstay of treatment is surgical, and in fact HBO is also an adjuvant and its clinical usefulness remains controversial (35,70). As also mentioned before in the prevention section, from a recent review by the Cochrane Collaboration group it was concluded that some evidence exists that HBO therapy improves the healing as adjuvant therapy in the treatment of ORN after hemi-mandibulectomy and reconstruction, and it prevents the development of ORN following tooth extraction from an earlier radiated jaw part (63). Figure 4. Open in new tabDownload slide Planning osteoradionecrosis (ORN) (3-dimensional [3D] planning). 3D visualization of radiation field for planning of resection of ORN of mandibular bone in a patient previously surgically treated for a T4N2c squamous cell carcinoma of the floor of mouth with a marginal mandible resection and bilateral neck dissection and post-operative radiotherapy to a maximum dose of 56 Gy. A) Visualization of the mandible with a pathological fracture due to ORN. B) Visualization of the 56 Gy planned target volume (PTV), in this case the highest radiation dose. C) Cutting planes planned just dorsal to the 56Gy PTV. D) 3D virtual planning of reconstruction with the patients’ fibula bone of the virtual resected mandible. Figure 4. Open in new tabDownload slide Planning osteoradionecrosis (ORN) (3-dimensional [3D] planning). 3D visualization of radiation field for planning of resection of ORN of mandibular bone in a patient previously surgically treated for a T4N2c squamous cell carcinoma of the floor of mouth with a marginal mandible resection and bilateral neck dissection and post-operative radiotherapy to a maximum dose of 56 Gy. A) Visualization of the mandible with a pathological fracture due to ORN. B) Visualization of the 56 Gy planned target volume (PTV), in this case the highest radiation dose. C) Cutting planes planned just dorsal to the 56Gy PTV. D) 3D virtual planning of reconstruction with the patients’ fibula bone of the virtual resected mandible. Figure 5. Open in new tabDownload slide Surgical treatment of osteoradionecrosis (ORN) after 3-dimensional virtual planning. Clinical pictures of the same patient as shown in Figure 4.A) Intra-oral view of the ORN of the mandible. B) Surgical exposure of pathological fracture of mandible. C) After resection of necrotic bone of the mandible using cutting guides based on the virtual planning as shown in Figure 4. D) View after placement of fibula in defect of mandible. Figure 5. Open in new tabDownload slide Surgical treatment of osteoradionecrosis (ORN) after 3-dimensional virtual planning. Clinical pictures of the same patient as shown in Figure 4.A) Intra-oral view of the ORN of the mandible. B) Surgical exposure of pathological fracture of mandible. C) After resection of necrotic bone of the mandible using cutting guides based on the virtual planning as shown in Figure 4. D) View after placement of fibula in defect of mandible. Pharmacological management is an additional therapeutic strategy for ORN, such as pentoxifylline, tocopherol, and clodronate (27,75). Pentoxifylline is used to dilate vessels and increase erythrocyte flexibility, both factors to enhance blood flow, as well as to reduce proliferation of dermal fibroblasts and to promote collagenase activity. Tocopherol (vitamin E) is a weak antioxidant able to act as a radical scavenger and also has an antifibrotic activity. Clodronate is a bisphosphonate that reduces osteoclasts numbers and activity and has an anti-inflammatory activity by reducing the levels of interleukin (IL)-1β, IL-6, and tumor necrosis factorα. The combination of these drugs has been shown to promote healing of ORN (Figure 6) (27,75,76). This approach is promising, but its efficacy has to be confirmed by other groups. Figure 6. Open in new tabDownload slide Pharmacological treatment of osteoradionecrosis (ORN) with Pentoclo protocol. A) Patient with ORN after surgical treatment of a T2N2b squamous cell carcinoma followed by postoperative radiotherapy to a maximum of 66 Gy. The ORNs did not respond to surgical debridement with pre and postoperative HBO. B) The patient was treated according to the pentoclo protocol. The pentoxifylline-tocopherol combination decreases the superficial fibrosis induced by radiotherapy. Potentiation by clodronate (PENTOCLO) appears to be effective in ORN of the mandible (70). The ORN responded to this therapy after a treatment period of 11 months. On two occasions softened necrotic bone was removed after spontaneous sequestration. Figure 6. Open in new tabDownload slide Pharmacological treatment of osteoradionecrosis (ORN) with Pentoclo protocol. A) Patient with ORN after surgical treatment of a T2N2b squamous cell carcinoma followed by postoperative radiotherapy to a maximum of 66 Gy. The ORNs did not respond to surgical debridement with pre and postoperative HBO. B) The patient was treated according to the pentoclo protocol. The pentoxifylline-tocopherol combination decreases the superficial fibrosis induced by radiotherapy. Potentiation by clodronate (PENTOCLO) appears to be effective in ORN of the mandible (70). The ORN responded to this therapy after a treatment period of 11 months. On two occasions softened necrotic bone was removed after spontaneous sequestration. Strategies to Promote Development and Funding for the New Research Since the 1989 NIH Development Consensus Conference on the Oral Complications of Cancer Therapies, significant progress has been made in the ability to reduce bone damage due to advances in radiation techniques, including optimizing of 3D treatment planning and IMRT. Currently, IMRT and its next step, proton therapy, have the greatest potential as a management strategy for prevention of jawbone damage in head and neck cancer patients. Nonetheless, many of these therapies still only offer partial reduction of the permanent injuries of healthy jaw bones. Other studies aim to prevent bone damage or to improve bone healing after radiation injury. Such studies will include improving surgical insight and operation techniques based on merging radiation field data with imaging data of damaged bone and 3D virtual planning data of the surgery to be performed. Such research efforts are very costly and need the involvement of researchers that have access to national and international scientific societies (eg, European Organisation for Research and Treatment of Cancer Head & Neck Cancer Group, European Society for Therapeutic Radiation Oncology, International Society for Stem Cell Research, Stem Cells in Development and Disease, and Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology). The same applies for randomized clinical trials assessing the potential benefit of HBO and pharmacologic management. Researchers performing such studies need to have access to a network that allows them to successfully compete for multinational translational grants from, for example, the National Institutes of Health and the European Framework Programs as well as to have access to sufficient large cohorts of well-defined patients with ORN or being at high risk of developing ORN. Only this way can sound, well-designed trials be performed, probably, because of the needed patient numbers, in a multicenter context. Fortunately, interest in growing in governmental, public, and private funding organizations as well as among researchers researching healthy aging, which increases the opportunities of getting such studies funded. This is also favorable because research aimed at prevention and reduction of the morbidity of cancer treatment fits well within the National Institutes of Health and European Framework programs. Funding Unrestricted educational grant support for the writing of this report was made available from the University Medical Center Groningen. Notes Affiliations of authors: Department of Oral & Maxillofacial Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (FKLS, MJHW, AV); Department of Oral Medicine, Carolinas Medical Center, Charlotte, NC (MTB); Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, Neag Comprehensive Cancer Center, UConn Health, Farmington, CT (DEP). F. Spijkervet has no conflicts of interest to declare. M. Brennan is a consultant for AFYX and Medimmune; none of this consulting activity is related to the content of this manuscript. D. 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Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com © The Author(s) 2019. Published by Oxford University Press.

Journal

JNCI Monographs – Oxford University Press

Published: Aug 1, 2019

Keywords: radiation therapy; head and neck cancer; necrosis; osteoradionecrosis; radiotherapy dosage; surgical procedures, operative; jaw; mandible; cancer therapy; toxic effect; head and neck; prevention; pharmacotherapy; dental clinics; conservative treatment; soft tissue; morbidity; radiotherapy, conformal; societies, scientific; immunologic adjuvants; pharmaceutical adjuvants; antibiotic prophylaxis; seizures; healthy aging; hyperbaric oxygenation; dental surgical procedures

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