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Is the Risk to Develop Osteoradionecrosis of the Jaws Following IMRT for Head and Neck Cancer Related to Co-Factors?

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Is the Risk to Develop Osteoradionecrosis of the Jaws Following IMRT for Head and Neck Cancer Related to Co-Factors? medicina Article Is the Risk to Develop Osteoradionecrosis of the Jaws Following IMRT for Head and Neck Cancer Related to Co-Factors? Eli Rosenfeld 1,*, Bassel Eid 2, Daya Masri 1, Aron Popovtzer 3, Aviram Mizrachi 4,5 and Gavriel Chaushu 1,6 1 Department of Oral & Maxillofacial Surgery, Beilinson Hospital, Rabin Medical Center, Petah Tikva 4941492, Israel; [email protected] (D.M.); [email protected] (G.C.) 2 The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; [email protected] 3 Sharett Institute of Oncology, Hadassah Medical Center, Jerusalem 9574401, Israel; [email protected] 4 Department of Otorhinolaryngology—Head and Neck Surgery, Rabin Medical Center, Petah Tikva 4941492, Israel; [email protected] 5 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel 6 Department of Oral and Maxillofacial Surgery, The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel Aviv University, Tel Aviv 6997801, Israel * Correspondence: [email protected]; Tel.: +972-50-7904090 Abstract: Background and Objectives: Determine the contribution of coexisting factors to the risk to develop Osteoradionecrosis (ORN) of the jaws among patients who have received radiotherapy by intensity modulated radiation therapy (IMRT) for head and neck cancer (HNC) between 2013 and 2016, in a single medical center. Materials and Methods: The records of all patients treated with IMRT for HNC between 2013 and 2016 in The Davidoff Center for the treatment and Research of Citation: Rosenfeld, E.; Eid, B.; Cancer in Rabin Medical Center—Beilinson hospital, Petah-Tikva, Israel were screened. Patients Masri, D.; Popovtzer, A.; Mizrachi, A.; who have received a minimum mean dose of 40 Gy to the oral cavity entered the research and their Chaushu, G. Is the Risk to Develop medical records were retrospectively reviewed. Collected background data included: age, gender, Osteoradionecrosis of the Jaws smoking, diabetes mellitus (DM), ASA score, mean and maximal radiation doses (Gy), and diseases Following IMRT for Head and Neck characteristics including histological diagnosis, primary tumor site, and disease stage. Results: A Cancer Related to Co-Factors? total of 1232 patients were surveyed. Out of all screened patients, 93 received a minimum mean dose Medicina 2021, 57, 468. https:// doi.org/10.3390/medicina57050468 of 40 Gy to the oral cavity. Out of the 93 patients, 7 (7.52%) developed ORN (ORN+) and 86 did not develop ORN (ORN−). Tumor type in all seven patients in the ORN+ group was Squamous Cell Academic Editor: Chung H. Kau Carcinoma (SCC). In three out of those seven patients (42.9%), the tumor was located in the mandible. Conclusions: within the limits of the relatively small cohort in the current study, we suggest that the Received: 20 March 2021 development of ORN due to Radiation therapy (RT) with IMRT is related significantly only to the Accepted: 28 April 2021 location of a tumor in the mandible. Other co-factors do not significantly increase the risk to develop Published: 11 May 2021 ORN when RT is delivered via IMRT. Publisher’s Note: MDPI stays neutral Keywords: osteoradionecrosis of the jaw; osteo-radionecrosis (ORN); intensity modulated radiation with regard to jurisdictional claims in therapy (IMRT) published maps and institutional affil- iations. 1. Introduction First description of the phenomenon of necrosis of the jaws post radiation therapy Copyright: © 2021 by the authors. later termed osteoradionecrosis (ORN) is attributed to Regaud in the early 1920s [1]. The Licensee MDPI, Basel, Switzerland. definition of ORN in recent literature is the presence of exposed bone that does not undergo This article is an open access article spontaneous healing for three months, and the lack of evidence of tumor recurrence [2]. distributed under the terms and The clinical findings and symptoms that accompany the exposure of necrotic bone conditions of the Creative Commons include pain and recurrent infections of the exposed bone and pus secretion. The presence Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ of exposed necrotic bone in the oral cavity can cause halitosis, impaired sense of taste and 4.0/). Medicina 2021, 57, 468. https://doi.org/10.3390/medicina57050468 https://www.mdpi.com/journal/medicina Medicina 2021, 57, x FOR PEER REVIEW 2 of 11 Medicina 2021, 57, 468 2 of 11 of exposed necrotic bone in the oral cavity can cause halitosis, impaired sense of taste and food impaction,food depending impaction, on depending the location on of the the location lesion, of it themight lesion, be associated it might be also associated with also with symptoms ofsymptoms trismus and/or of trismus paresthesia. and/or [3] paresthesia. [3] This phenomenonThis phenomenon occurs almost occurs exclusively almost in exclusively the mandible in the (Figure mandible 1). In (Figure the minor-1). In the minority ity of cases whereof cases it occurs where in it occursthe maxilla, in the ORN maxilla, progresses ORN progresses more slowly, more and slowly, the extent and the of extent of the the bony damagebony is damage usually isless usually severe. less Differ severe.ences Differences between the between jaws are the probably jaws are related probably related to the fact thatto the the blood fact that supply the bloodto the mandib supplyle to is the significantly mandible reduced is significantly compared reduced to the compared to maxilla and thatthe maxillathe mandible and that absorbs the mandiblegreater pressure absorbs and greater load compared pressure andto the load maxilla compared to the [4]. maxilla [4]. A B Figure 1. MandibularFigure 1. ORN Mandibular following ORN mandibulotomy following mandibulotomy and radiotherapy and for radiotherapy squamous cellfor carcinomasquamous ofcell the carci- base of tongue. (A) clinical imagenoma demonstrating of the base of dehiscence tongue. (A of) clinical the soft image tissue demonstrating and exposure of dehiscence necrotic bone of the on soft the inferiortissue and border of the left exposure of necrotic bone on the inferior border of the left mandibular parasymphysis and body mandibular parasymphysis and body and (B) a 3-dimensional reconstruction of the CT demonstrating sequestration of the and (B) a 3-dimensional reconstruction of the CT demonstrating sequestration of the inferior man- inferior mandibular border. dibular border. The histopathology of ORN is characterized by a lack of osteoblasts, and replacement The histopathology of ORN is characterized by a lack of osteoblasts, and replacement of normal bone marrow with fibrotic tissue. There is apparent absence of inflammatory of normal bone marrow with fibrotic tissue. There is apparent absence of inflammatory cells, while a multitude number of bacteria (mostly anaerobic) and fungus can be detected cells, while a multitude number of bacteria (mostly anaerobic) and fungus can be detected in ORN specimens [5,6]. in ORN specimensThe [5,6]. reported prevalence of the phenomenon is variable, ranging between 0.4% and The reported56.0% prevalence [2,7]. With of the the implementation phenomenon is of variable, Intensity ranging Modulated between Radiation 0.4% and Therapy (IMRT) 56.0% [2,7]. Within the the treatment implementation of head andof Intensity neck cancers Modula (HNCs),ted Radiation a significant Therapy decrease (IMRT) in the extent of in the treatmentORN of development head and neck can cancers be seen, (HNCs), with newer a significant reports rangingdecrease between in the extent 5% and of 15%, mostly ORN developmentin patients can be older seen, than with 55 newer [2]. reports ranging between 5% and 15%, mostly in patients older thanThe risk55 [2]. factors for the development of ORN include local, systemic and also genetic The riskfactors factors [for8–11 the]. Localdevelopment factors include of ORN tumor include size, local, xerostomia, systemic neglectedand also genetic dental status, poor factors [8–11].oral Local hygiene factors and include associated tumor localsize, xerostomia, trauma, such neglected as tooth dental extraction/surgery status, poor before or oral hygiene afterand associated radiotherapy. local Systemic trauma, such factors as includetooth extraction/surgery immune system malfunction,before or after malnutrition, radiotherapy.peripheral Systemic vascularfactors include disease, heavyimmune smoking, system and malfunction, excessive alcohol malnutrition, consumption. pe- Generally, ripheral vascularthe risk disease, of developing heavy smoking, ORN and is lower excessive in edentulous alcohol consumption. patients. The Generally, dose of radiation is the risk of developingobviously ORN also is related lower toin theedentu developmentlous patients. of ORNThe dose which of radiation is more prevalent is obvi- in patients ously also relatedwho haveto the been development exposed toof 60–70ORN Gywhich during is more radiation prevalent therapy in patients (RT) and who have received have been exposedchemotherapy to 60–70 inGy addition during toradi RT.ation therapy (RT) and have received chemo- therapy in additionThe to pathogenesisRT. of ORN is not completely understood. In 1970 Meyer suggested The pathogenesisthe Radiation-induced of ORN is not Osteomyelitis completely understood. theory [12], In according 1970 Meyer to which, suggested the radiationthe causes Radiation-inducedchanges Osteomyelitis and cellular death theory in soft[12], tissue according leading to towhich, dehiscence the radiation and bone causes exposure,
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