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

Background. Osteoradionecrosis of the jaw (ORN) is an infrequent yet potentially devastating complication of radiation therapy to the head and neck region.Treatment options include antimicrobial therapy, local sequestrectomy, resection, and the use of hyperbaric oxygen (HBO). Published data on ORN are difficult to compare because of the lack of a universally accepted classification and staging system, and the literature on the use of HBO to either prevent or successfully manage ORN is controversial and inconclusive. Therefore, we aimed to establish a standard approach for using HBO at our institution. Materials and Methods. A literature search was conducted of articles published in the English language between January 1980 and January 2016. Retrieved articles were evaluated by two independent reviewers. Isolated case reports, abstracts, case series, review articles, and cohort studies without a control group were excluded; summary data were extracted from the remaining studies. A panel of experts from Head and Neck Oncology and Oral Medicine from the Dana-Farber Cancer Institute and Brigham and Women’s Hospital reviewed the summary data and established multidisciplinary guidelines on the use of HBO for the prevention andmanagement of ORN. Results. Seven studies were evaluated and reviewed by the multidisciplinary panel. There was no consistent evidence in support of HBO for either the prevention or management of ORN. Conclusion. Based on the available evidence and expert opinion, routine use of HBO for the prevention or management of ORN is not recommended and is rarely used at our institution. The Oncologist 2017;22:343–350 Implications for Practice: The Division of Head and Neck Oncology of Dana-Farber/Brigham and Women’s Cancer Center does not recommend the routine use of HBO for the prevention or management of ORN. Adjunctive HBO may be considered for use on a case-by-case basis in patients considered to be at exceptionally high risk who have failed conservative therapy and subsequent surgical resection. INTRODUCTION Osteoradionecrosis of the jaw (ORN) is an infrequent yet potentially devastating complication of head and neck radiation therapy (RT). ORN is defined as non-healing exposed necrotic bone in a previously irradiated site that has been present for at least 3 months [1]. ORN may be associated with pain, infection, disability, and a diminished quality of life [2, 3]. ORN can develop spontaneously without a clear precipitating event, or it can be secondary to denture-induced trauma or periodontal disease [1]. However, most cases develop following dental extractions [1, 4]. The median time reported from initiation of RT to ORN onset is 13 months (range: 2–122 months) [4]. For this reason, it is standard of care for patients to undergo dental evaluations prior to RT and to have infected teeth, teeth at high risk for infection, or teeth with a poor prognosis extracted at this time Correspondence: Robert Haddad, M.D., Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA. Telephone: 617-632-3090; e-mail: Robert_haddad@dfci.harvard. edu; or Hani Mawardi, B.D. S. , Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA. Telephone: 617-632-3090; e-mail: hmawardi@partners.org Received July 27, 2016; accepted for publication October 05, 2016; published Online First on February 16, 2017. Oc AlphaMed Press 1083-7159/2016/$20.00/0 http://dx.doi. org/10.1634/theoncologist.2016-0298 The Oncologist 2017;22:343–350 www.TheOncologist. com Oc AlphaMed Press 2017 Head and Neck Cancer [5–7]. It is also recommended that the remaining dentition be well-maintained subsequent to completing RT in order to avoid future extractions and thus reduce the risk of developing ORN [6]. To date, many preventive strategies for ORN have been proposed that have yet to be validated by high-level evidence. These measures include, but are not limited to, pre-RT dental evaluation and treatment, antibiotic treatment following post-RT extractions, pentoxifylline and tocopherol prophylaxis, or hyperbaric oxygen (HBO) prophylaxis [8, 9]. Once diagnosed, treatment of ORN ranges from conservative surgical approaches, such as local surgical debridement and sequestrectomy, to more extensive surgical intervention, such as resection with or without osteomyocutaneous flaps. Surgical approaches may be complemented by adjunctive medical therapies such as antibiotics (topical and/or systemic), pentoxifylline and tocopherol, or HBO [8, 10, 11]. Currently, there are no consensus statements or universal guidelines for the prevention or management of ORN, leaving clinicians and patients faced with uncertainty as to best-care decisions. The use of HBO to treat ORN was initially suggested by Marx in 1983 [12] and was later proposed as a means to prevent ORN in 1985 [13]. The proposed mechanism focuses on the potential role of HBO to facilitate wound healing by increasing local tissue oxygen tension, resulting in enhanced collagen synthesis, angiogenesis, bone regeneration, and oral tissue epithelization to overcome the underlying pathogenesis of ORN that consists of hypoxia, hypocellularity, and hypovascularity due to the effects of RT [10, 14]. Many clinicians have subsequently utilized HBO prior to dental extractions in order to prevent ORN or as monotherapy or adjunctive therapy for treating existing ORN [15–20]. A recent Cochrane systematic review concluded that there was “some evidence” to support the use of HBO to prevent the development of ORN following tooth extraction in an irradiated field, but further research is necessary to validate this approach [21]. Considering the lack of irrefutable supporting evidence, the high cost of treatment (average cost of 1 HBO session5 $1,333; average cost of 30 sessions5 $40,000; personal communication with billing departments of the Norman Knight Hyperbaric Medicine Center, Boston, MA, and St. Elizabeth’s HBO Medical Center, Brighton, MA), and the limited number of HBO facilities, the use of HBO in this clinical setting remains controversial. The objective of this report is to provide pragmatic and evidence-based clinical guidelines for the use of HBO at our institution to prevent and treat ORN based on the current available literature. MATERIALS AND METHODS A review of English language publications reporting on ORN prevention and treatment utilizing HBO between January 1980 and January 2016 was performed using PubMed and Medline. Ninety citations were identified and evaluated for content and level of evidence by two independents reviewers (A.S. and G.J.H.). Inclusion criteria required both of the following: (a) articles published in the English language and reporting on ORN prevention or treatment using HBO and (b) randomized clinical trials and cohort studies (prospective or retrospective) with a control group. Exclusion criteria were as follows: (a) studies not published in the English language and (b) single case reports, case series, review articles, and cohort studies without a control group. Each study was evaluated for the following parameters: study design, study endpoints, ORN stage, and ORN prevention and treatment regimens. Each study was also evaluated for overall strengths, limitations, and level of evidence according to the Centre for Evidence-Based Medicine system [22]. An expert panel composed of medical oncologists, surgical oncologists, radiation oncologists, and oral medicine specialists met in September 2015 to review and discuss the summary data and establish multidisciplinary guidelines. RESULTS A total of seven studies met the inclusion criteria: three for prevention and four for management of ORN (Fig. 1, Table 1). The Use of HBO for the Prevention of ORN Prior to and Following Dental Extraction(s) in Previously Irradiated Patients There were three studies in this category: one randomized clinical trial and two retrospective cohort studies [13, 15, 16]. In the 1985 study by Marx et al. [13] including 3 centers, 74 patients who had previously received RT and were scheduled for dental extraction(s) were randomized to receive either HBO only (without antibiotics) or preoperative and postoperative oral antibiotics only (control arm). Patients in the HBO arm received 20 sessions (dives) of HBO prior to dental extractions followed by an additional 10 HBO sessions following dental extractions, while those in the antibiotic arm received 1 million units of aqueous penicillin G intravenously prior to dental extractions followed by 500 mg of phenoxymethyl penicillin 4 times daily for 10 days post dental extractions. ORN was documented in 2 of 37 patients (5%) in the HBO arm compared with 11 of 37 patients (30%) in the antibiotic arm. Vudiniabola et al. [15] in 1999 performed a retrospective cohort study and included 37 patients who were post RT, scheduled for dental extraction(s), and at risk for ORN. Thirty patients (30/37; 81%) received HBO according to the protocol Figure 1. Flow diagram of literature search and study selection. Oc AlphaMed Press 2017 344 Osteoradionecrosis of the Jaw