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Osteoradionecrosis - Mandibular

Osteoradionecrosis - Mandibular

Osteoradionecrosis - Mandibular

INTRODUCTION

Treatment Protocol Guidelines

The following hyperbaric medicine treatment protocol is based upon the recommendations of the Hyperbaric Oxygen Committee of the Undersea and Hyperbaric Medical Society.  Clinical protocols and/or practice guidelines are systematically developed statements that help physicians, other practitioners, case managers and clients make decisions about appropriate health care for specific clinical circumstances.  

Protocols allow health providers to offer evidence-based, appropriate, standardized diagnostic treatment and care services to patients undergoing hyperbaric oxygen therapy (HBOT). This section discusses osteoradionecrosis of the mandible (ORN). Evidenced-based medicine offers clinicians a way to achieve improved quality, improved patient satisfaction, and reduced costs.  Utilization Review should be initiated when clinical decisions result in deviation from, or modification of, treatment protocols.  This includes any course of treatment at or above the recognized threshold limits.  

Medical Necessity

Medicare.gov defines “medically necessary” as “health-care services or supplies needed to prevent, diagnose, or treat an illness, injury, condition, disease, or its symptoms and that meet accepted standards of medicine.” 

The following condition meets coverage indications per the National Coverage Determination (NCD) 20.29.[1] Continued HBOT therapy without documented evidence of effectiveness does not meet the Medicare definition of medically necessary treatment. Thorough re-evaluation should be made at least every 30 days for documentation of response to therapy. 

TREATMENT PROTOCOL


 HBO request requirements checklist |   Sample Physician Order | $ ICD-10 Crosswalk   |  Treatment Table 

BackgroundDelayed effects of radiation are a complication of modern radiotherapy that can be ameliorated with hyperbaric oxygen therapy. Some examples of delayed radiation effects include soft tissue radionecrosis, osteoradionecrosis (ORN), radiation cystitis, radiation proctitis, and laryngeal chondroradionecrosis. The basic pathophysiology of delayed radiation tissue damage is an obliterative endarteritis with resultant tissue hypoxia and secondary fibrosis. ORN can be characterized according to the Marx classification.[2] HBOT is an effective adjunctive therapy for existing ORN Marx Stage I-III (Figures 1 and 2).[1] 

Goals of HBOT

  • Reduce tissue fibrosis and breakdown by inducing neovascularization and improving tissue oxygenation 
  • Prevent wound dehiscence following soft tissue reconstruction in previously irradiated areas

Diagnosis

  • Osteoradionecrosis is the result of avascular, aseptic necrosis in a previously irradiated field. Irradiated bone becomes exposed through a wound in the overlying skin or mucosa. [3] 
  • After radiation to the mandible, salivary glands are non-functional. Saliva is imperative for tooth health. Mandibular teeth (with a single blood supply) tend to suffer most and begin to breakdown. The underlying mandible may also breakdown and become exposed.
  • Clinical findings include pain on mastication, fibrotic skin, orocutaneous fistula, exposed mandible, trismus, infection, pathologic fracture, and/or bad breath
  • Radiographic findings include moth-eaten appearance of the mandible, pathological fractures 
  • The teeth or mandible involved must be within the radiation ports

Hyperbaric Criteria

  • Referral documenting confirmed diagnosis of osteoradionecrosis (This generally comes from an oral surgeon.)
  • History and documentation of radiation treatment to the region of the pathology including laterality.
  • Radiation treatment terminating at least 6 months prior to onset of signs, symptoms, or planned surgical intervention at the site.

Evaluation 

  • Comprehensive history, to include:
    1. Date cancer diagnosed
    2. Date radionecrosis diagnosed
    3. Type, amount, number of treatments and location of the radiation 
    4. Radiation date span
    5. Previous treatment or therapies
  • Obtain the radiation-oncology reports 
  • Physical examination
  • Labs to order or review:
    1. CBC
    2. Serum Albumin
    3. Pre-albumin
    4. Sedimentation Rate
    5. C-reactive protein
  • Wound photographs
  • Chest x-ray: order or review
  • ECG: order or review
  • Determine present oncological status
  • Evaluation of tympanic membranes pre- and post-treatment as needed
  • Baseline visual acuity assessment
  • Smoking/nicotine cessation
  • Nutritional screening. These patients generally lose weight after radiation and may be continuing to lose weight with the oral lesions. Be sure to monitor overall weight loss, and include a statement that says weight is stable, increasing, or decreasing.
  • Coordination of hyperbaric therapy and surgical procedures, in conjunction with referring oral-maxillofacial surgeon.
    • Classify mandibular necrosis with the Marx scale to describe the severity of the ORN. [2][4] 
      • Stage I ORN: patients with exposed bone which has been chronically present or which developed rapidly.
      • Stage II ORN: patients who do not respond favorably to 30 pre-operative HBOT treatments, or when a more major operative debridement is required.
      • Stage III ORN: Presence of orocutaneous fistulae, evidence of lytic involvement extending to the inferior mandibular border, full thickness bone damage or pathologic fracture. Usually requires complete resection and reconstruction with free tissue transfer. There are 2 sources of free flaps for this repair. One in a rib flap (with artery and vein) and the second is a fibular free flap (with artery and vein) If mandibular resection is anticipated, patients are advanced to Stage III from outset. 
  • Rule out cancer re-occurrence or residual tumor when possible. 

Treatment

Stage I:
  • Consists of HBOT sessions followed by minor bony debridement, then additional HBO sessions
  • HBOT:
    • 2.5 ATA for 90 minutes of oxygen breathing with two air breaks (may be 5 or 10 minutes in length) at the 30 and 60-minute portions of oxygen breathing (Table 3)
    • HBOT once daily for 30 treatments
  • Surgery:
    • Minor bony debridement
  • HBOT (to complete the Marx treatment protocol)
    • If adequate response, continue with 10 additional daily HBOT and follow patient to complete clinical resolution
    • If little or no improvement after 30 treatments, the patient may be advanced to stage II in consultation with the oral/maxillofacial surgeon.  

Stage II:

  • Consists of HBOT (30 treatments) followed by more radical surgical debridement, then additional HBOT (10 postoperative treatments)
  • Surgery:
    • Stage II patients receive a more aggressive surgical debridement, immediately followed by 10 postoperative daily HBOT. 
    • Surgery for stage II patients must maintain mandibular continuity.
    • If mandibular segmental resection is required, patients are advanced to stage III 

Stage III:

  • Consists of 30 preoperative HBOT, followed by transoral mandibular resection then additional 10 postoperative HBOT
  • Patients who originally classified as stage I or II who fail the initial therapy above, or patients who present initially with serious signs of pathologic fracture, orocutaneous fistulae, or evidence of lytic involvement extending to the inferior mandibular border, are treated as stage III.
  • Surgery:
    • Mandibular segmental resection and eradication of all necrotic bone are planned as part of the treatment. The usual surgery involves a free bone flap with attached soft tissue, and/or extensive titanium plate and screw reconstruction (Figure 3). If present, orocutaneous fistula or large tissue loss are also surgically addressed in this phase. 
  • After surgical resection and HBOT post-resection, the patient is advanced to stage III-R (reconstructive protocol)   

Stage III-R

  • Consists of mandibular reconstruction and additional HBOT 
  • After a period of several weeks following completion of stage III, definite mandibular bony reconstruction with techniques such as free flaps or myocutaneous flaps is conducted
  • Discuss with the oral/maxillofacial surgeon whether 10 postoperative treatments should follow in order to support initial free tissue flap.

For all patients

  • Wound photography post-reconstruction
  • Evaluation of tympanic membranes pre- HBOT and as needed
  • Smoking Cessation

Follow-Up

  • Visual acuity assessment for progressive myopia on a weekly basis (See topic "Visual Acuity and HBOT")
  • Wound assessment and photography as indicated

Treatment Threshold

30 – 60 treatments (Peer review should be requested after 60 treatments)  
Coding
Refer to the ICD-10 Guideline for the appropriate ICD-10 code
Comments
  • If the patient has diabetes, blood glucose should be checked within one 1 hour prior to treatment and post-HBOT by unit personnel. 
  • Avoid petroleum based dressings and ointments whenever possible. If these are a necessary part of the surgical dressing, ensure that they are not exposed and are completely covered with 100% cotton.
Primary Sources: Whelan and Kindwall [5]Weaver [6][7]
Fig. 1. Mandibular osteoradionecrosis. Marx Stage I with exposed mandible. By Worth E.R., M.D.
Fig. 2. Mandibular osteoradionecrosis. Marx Stage III with orocutaneous fistula. By Worth E.R., M.D.
Fig. 3. Mandibular reconstruction. By Worth E.R., M.D.

DOCUMENTATION 

Radiation doses in excess of 40 Gray (4,000 cGy) are more commonly associated with compromised/delayed healing and persistent soft tissue/ integumentary breakdown within a previously irradiated field that has failed conservative and/or surgical management. The role of hyperbaric oxygen is one of overcoming hypovascular - hypocellular - hypoxic tissue bed and the late-radiation effects. Acute inflammatory responses to ongoing or recently completed radiation therapy need to be differentiated. Relieve the radiotherapy-induced hypoxic/ischemic state by stimulating angiogenesis, thereby overcoming radiation-induced obliterative endarteritis. Below we explain in detail what needs to be documented and provide sample statements that can be adapted to suit your needs. See also:

  •   HBOT request requirements checklist    

History 

Sample history for osteoradionecrosis is shown below: 

"Mr. Smith had a diagnosis of squamous cell cancer of the left side of the tongue. His radical neck surgery was in May, 2017. This was followed by 3 rounds of chemotherapy and 40 treatments of external beam electron therapy. The dosage ports were reviewed with the oral surgeon. He had an overall dose of 6,500 cGy with a boost at the base of the tumor to a total dose of 7,800 cGy. He comes to us now (10 months after radiation has finished) with a large area of visible mandible. We are asked to provide HBOT support for surgical resection and repair."

Documentation should include:

  • An initial assessment including a history and physical that clearly substantiates the condition for which HBOT is recommended.
  • Documentation of total radiation dose
  • Documentation of any prior medical, surgical and/or hyperbaric treatments.
  • Past medical records must support history of radiation therapy at the site identified by anatomical location.
  • Documentation of optimization of nutritional status

Physical Exam

  • Evidence of radiation therapy at the site identified by anatomical location (e.g., "Mrs. Smith has a permanent sunburn within the radiation tattoo marks over her left lateral mandible. The skin is taught and there are scattered telangiectasis noted within this area. There is no noted hair growth. The skin appears thin and friable.") You have just described the hallmark physical signs of radiated tissue.
  • Measure and describe the non-responding wound within the previously radiated field.
  • Clearly state what the intended clinical course will be.
  • Note any prior failure of definitive coverage attempts, flap or graft.

Impression

  • Osteoradionecrosis of the Mandible See ICD-10 Crosswalk

Plan 

"For preventing wound healing complications in heavily irradiated tissue areas, in the face of established osteoradionecrosis of the mandible, we treat patients with 30 hyperbaric oxygen treatments at 2.0 or 2.4 ATA, breathing oxygen for 90 to 120 minutes. The patient then undergoes surgical repair followed by 10 or more treatments postoperatively, until the wound shows signs of continued healing."

Risk and Benefit of Hyperbaric Oxygen Treatment

Please refer to topic "Documentation HBO: Risks and Benefits"

Indication for Hyperbaric Oxygen Therapy (HBOT)

"Delayed effects of radiation are a complication of modern radiotherapy that can be well treated with hyperbaric oxygen therapy. Some examples of delayed radiation effects include soft tissue radionecrosis, osteoradionecrosis, radiation cystitis, radiation proctitis, and laryngeal chondroradionecrosis. The basic pathophysiology of delayed radiation tissue damage is endarteritis with resultant tissue hypoxia and secondary fibrosis. 

Delayed radiation complications are often manifest as non-healing wounds located in previous irradiated areas and are precipitated by an additional insult such as surgery or trauma within the field of radiation. Hyperbaric oxygen has been shown to induce neovascularization and increase cellularity in irradiated and other hypoxic tissues. The success with randomized controlled studies in patients with mandibular osteoradionecrosis is clearly noted. Dental extractions or other surgical procedures are fraught with high complication rates when performed in heavily irradiated tissues without the benefit of preoperative hyperbaric oxygen therapy."

Sample Order

  •  See Sample Physician Order

CLINICAL EVIDENCE AND RECOMMENDATIONS  

  • 1BFor patients with ORN Stage I, II and III, we recommend HBOT as an adjunctive therapy (Grade 1B)
  • Stage I: HBOT followed by minor debridement, then additional HBOT
  • Stage II: HBOT followed by more radical surgical debridement, then additional HBO;
  • Stage III: HBOT followed by mandibular resection, additional HBOT, then mandibular reconstruction and additional HBOT 
    • Rationale: A small percentage of patients treated with radiation for head and neck cancers will develop osteoradionecrosis (ORN) of the jaw. Patients treated with more than 6000 centigray (cGy) of radiation have an approximately 9% incidence of developing mandibular ORN.[2] Radiation doses in excess of 40 Gray (4,000 cGy) are more commonly associated with compromised/delayed healing and persistent soft tissue/ integumentary breakdown within a previously irradiated field that has failed conservative and/or surgical management. 
    • The Marx scale classifies mandibular necrosis and is used to describe the severity of the ORN.[2] Stage I ORN: patients with exposed bone. Stage II ORN: patients who do not respond favorably to 30 pre-operative HBOT treatments and a minor debridement (usually in the dentist/surgeon office), or when a more major operative debridement is required. Stage III ORN: presence of orocutaneous fistulae, evidence of lytic involvement extending to the inferior mandibular border, full thickness bone damage or pathologic fracture. Usually requires complete resection and reconstruction with free flap transfer.[4] If mandibular resection is anticipated, patients are advanced to Stage III from outset. 
    • Use of HBOT for management as an adjunctive therapy to treat ORN is supported by moderate certainty evidence (evidence level B).[8][9][10] The role of hyperbaric oxygen is one of overcoming hypovascular - hypocellular - hypoxic tissue bed and the late-radiation effects. Acute inflammatory responses to ongoing or recently completed radiation therapy need to be differentiated. 
    • A frequently expressed concern by those considering hyperbaric oxygen for a patient with radiation injury is the fear that hyperbaric oxygen will somehow accelerate malignant growth or cause a dormant malignancy to be reactivated. An overwhelming majority of both clinical reports and animal studies reviewed showed no enhancement of cancer growth.[9]
    • Coverage: Medicare covers perioperative use of HBOT as an adjunctive therapy for existing ORN Marx Stage I-III. Data to justify HBOT prophylaxis for osteoradionecrosis in a previously irradiated mandible undergoing tooth extraction is lacking at this time; subsequently this is a non-covered service. See section on 'Coverage and Reimbursement' below.

CODING

ICD-10 Coding 

COVERAGE AND REIMBURSEMENT

  • Medicare covered condition: Medicare covers perioperative use of HBOT as an adjunctive therapy for existing ORN Marx Stage I-III. Prerequisite for treatment includes history of radiation treatment to the region of the documented injury, terminating at least 6 months prior to onset of signs or symptoms or planned surgical intervention at the site. The recommended daily treatments are designed around the stages of radionecrosis and typically last 90-120 minutes at 2.0 to 2.5 ATA. The duration of HBOT therapy for these patients is highly individualized but is not expected to exceed 4-8 weeks therapy. The Marx mandibular osteoradionecrosis protocol extends from 30-60 treatments based on stage I-III, adhering to the established principle that all necrotic bone must be debrided. No demonstrable evidence of improvement post two 30 day periods of HBOT (2.0-2.5 ATA, for 90 to 120 minutes, 5 days per week) suggests lack of benefit and subsequent treatments will be denied as not medically reasonable and necessary. [11]
  • Medicare non-covered conditions: In a 2019 randomized control trial, HBOT was used to determine the incidence of delayed osteoradionecrosis in an irradiated mandible after tooth extraction and/or implant placement. At this time, there is no data to support HBOT prophylaxis for osteoradionecrosis in a previously irradiated mandible undergoing tooth extraction.[12] Prophylaxis is a non-covered service. HBOT is not covered to prepare the patient for dental extraction when radiation therapy has been done less than 6 months prior to extraction/implant. [11] We know of wound care/ HBOT clinics who view the need for teeth extraction (without visible mandible) as a form of soft tissue radiation necrosis where there is evidence of a highly radiated field that will need a surgical repair. Since there are no open wounds, the HBOT regimen would follow a Marx protocol with 20 preoperative treatments, then following surgery for 10 postoperative treatments.

APPENDIX

Summary of Evidence

Use of HBOT as an adjunctive therapy for existing ORN Marx Stage I-III.

Systematic reviews

  • A 2016 Cochrane systematic review [8] included 14 trials (753 participants). A meta-analysis of three RCTs showed that there was some moderate quality evidence that HBOT was more likely to achieve mucosal coverage with osteoradionecrosis (ORN) (risk ratio (RR) 1.3; 95% confidence interval (CI) 1.1 to 1.6, P value = 0.003, 246 participants, 3 studies). There was also moderate quality evidence of a significantly improved chance of wound breakdown without HBOT following operative treatment for ORN (RR 4.2; 95% CI 1.1 to 16.8, P value = 0.04, 264 participants, 2 studies). As for bony continuity, 1 RCT (104 participants) showed that the experimental group (HBOT) had statistically significant higher chance of establishment of bony continuity compared to the control group (P value = 0.002). 1 RCT (74 participants) contributed results to healing of tooth sockets following extraction in irradiated field at six months [8]. There was an increased chance of successful healing with HBOT compared to the control group (P value = 0.02)
  • A 2016 systematic review [13] included 7 studies (RCTs and observational studies) that analyzed HBOT in ORN management. Authors concluded that HNO‐DF/BWCC does not recommend the routine use of HBOT for the prevention or management of ORN. Adjunctive HBOT 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. The highest level of evidence available to date on the management of ORN using HBOT comes from the Annane et al. 2004 multicenter trial. The trial was terminated early due to worse outcomes in the HBOT arm (19% resolution with HBOT versus 32% resolution with placebo). This study did not include the same RCTs evaluated by Bennett et al [8] and thus generated different conclusions. The Annane study was flawed by design. This study demanded that the ORN lesions would close without any surgical procedure, by HBOT alone, in order to be counted as successful. Marx, in original publications, recognized that HBOT was adjunctive to surgical procedures to extirpate dead bone and close the resulting defects.

Guidelines:

  • The 2014 UHMS HBO Therapy Indications Book (Guidelines) [9] and the 2017 European Committee for Hyperbaric Medicine Guidelines [10] support the use of HBOT as an adjunctive therapy to treat ORN, and although the guidelines use different evidence grading methodologies, they are in agreement regarding strength of recommendation.  See table below:

HBOT for Mandibular Osteoradionecrosis (ORN)

UHMS, 2014 ECHMG, 2017

HBOT followed by debridement and additional HBO for Stage I Mandibular ORN

AHA Class Ib  Grade 1B

HBOT followed by a more radical surgical debridement for Stage II Mandibular ORN

AHA Class Ib  Grade 1B
Mandibular resection followed by HBOT, then mandibular reconstruction and HBOT in the treatment of Stage III Mandibular ORN AHA Class Ib  Grade 1B

Observational

  • A 2018 retrospective study by Jenwitheesuk et. al. [14] aimed to determine the benefits of adjunctive treatment of HBOT in ORN (n=84 patients). Authors found that HBO improved wound healing of ORN patients with stages I-III. 
  • A 2017 observational study by Dieleman et al [15] evaluated the success of HBOT and surgery in the treatment of mandibular osteoradionecrosis (ORN) in relation to the extent of the ORN. Twenty-seven patients with ORN with a history of primary oral or base of the tongue cancer who had been treated with radiation therapy with curative intent between 1992 and 2006, with a radiation dose to the mandible of ≥50Gy. The ORN was staged according to the classification of Notani et al. The time from completion of radiation therapy to the development of ORN varied (median 3 years). Forty HBOT sessions were offered. After HBOT alone, 3 of 11 stage I lesions, 0 of 8 stage II lesions, and 0 of 8 stage III lesions had healed (P=0.0018). An absolute incidence of 5.3% ORN was found in this population. Of all sites irradiated in this study, the floor of the mouth was most associated with ORN (8.6%), whereas the cheek was least associated (0%). Based on the results of this study, HBOT can be recommended for stage I and II ORN and for selected cases of stage III ORN (evidence level C)
  • A 2016 observational study by Niezgoda et. al. [16] analyzed the effect of HBOT on a cohort of patients (588 participants) with ORN and found that 92% presented with improved scores. 

HBOT prophylaxis for osteoradionecrosis

Randomized clinical trials (RCT)

  • A 2019 RCT (100 analyzed patients) compared effect of prophylactic HBOT on the incidence of ORN in patients who required dental extractions or implant placement in the mandible with prior radiation therapy >50 Gy. There was no statistically significant difference between both groups.The incidence of ORN at 6 months was 6.4% and 5.7% for the HBOT and control groups, respectively (odds ratio, 1.13; 95% confidence interval, 0.14-8.92; P = 1). Authors concluded that the low incidence of ORN makes recommending HBOT for dental extractions or implant placement in the irradiated mandible unnecessary.[12]

REVISION UPDATES

DateDescription
4/22/19Updated section on 'Clinical Evidence and Recommendations' with recent studies. Added section 'Coverage and Reimbursement'
5/21/19Updated section on 'Documentation'. Added figures


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REFERENCES

  1. CMS. National Coverage Determination (NCD) for Hyperbaric Oxygen Therapy (20.29) . 2017;.
  2. Hanley, Mary; Cooper, Jeffrey et al. Hyperbaric, Chronic Refractory Osteomyelitis StatPearls. 2017;.
  3. Lambade PN, Lambade D, Goel M et al. Osteoradionecrosis of the mandible: a review. Oral and maxillofacial surgery. 2013;volume 17(4):243-9.
  4. Lyons A, Ghazali N et al. Osteoradionecrosis of the jaws: current understanding of its pathophysiology and treatment. The British journal of oral & maxillofacial surgery. 2008;volume 46(8):653-60.
  5. Harry T. Whelan, Eric Kindwall et al. Hyperbaric Medicine Practice 4th Edition Best Publishing Company. 2017;volume fourth():.
  6. Weaver L . "Hyperbaric Oxygen Therapy Indications” Best Publishing Company, North Palm Beach, FL . 2014;volume 469(13th Edition,):.
  7. John J. Feldmeier, MD FACRO, FUHM et al. Undersea and Hyperbaric Medical Society, Hyperbaric Oxygen Indications, 13th edition: Delayed Radiation Injuries: Soft Tissue and Bony Necrosis . 2014;.
  8. Bennett MH, Feldmeier J, Hampson NB, Smee R, Milross C et al. Hyperbaric oxygen therapy for late radiation tissue injury. The Cochrane database of systematic reviews. 2016;volume 4():CD005005.
  9. Undersea and Hyperbaric Medical Society Hyperbaric Oxygen Committee,, et al. Hyperbaric Oxygen Therapy Indications . 2014;.
  10. Mathieu, Daniel; Marroni, Alessandro; Kot, Jacek et al. Tenth European Consensus Conference on Hyperbaric Medicine: recommendations for accepted and non-accepted clinical indications and practice of hyperbaric oxygen treatment. Diving and hyperbaric medicine. 2017;volume 47(1):24-32.
  11. Novitas Solutions, Inc et al. Local Coverage Determination for Hyperbaric Oxygen (HBO) Therapy (L35021) . 2015;.
  12. Shaw RJ, Butterworth CJ, Silcocks P, Tesfaye BT, Bickerstaff M, Jackson R, Kanatas A, Nixon P, McCaul J, Praveen P, Lowe T, Blanco-Guzman M, Forner L, Brennan P, Fardy M, Parkin R, Smerdon G, Stephenson R, Cope T, Glover M et al. HOPON (Hyperbaric Oxygen for the Prevention of Osteoradionecrosis): A Randomized Controlled Trial of Hyperbaric Oxygen to Prevent Osteoradionecrosis of the Irradiated Mandible After Dentoalveolar Surgery. International journal of radiation oncology, biology, physics. 2019;.
  13. Sultan A, Hanna GJ, Margalit DN, Chau N, Goguen LA, Marty FM, Rabinowits G, Schoenfeld JD, Sonis ST, Thomas T, Tishler RB, Treister NS, Villa A, Woo SB, Haddad R, Mawardi H et al. 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. The oncologist. 2017;volume 22(3):343-350.
  14. Jenwitheesuk K, Mahakkanukrauh A, Punjaruk W, Jenwitheesuk K, Chowchuen B, Jinaporntham S, Uraiwan K, Limrattanapimpa P et al. Efficacy of Adjunctive Hyperbaric Oxygen Therapy in Osteoradionecrosis. BioResearch open access. 2018;volume 7(1):145-149.
  15. Dieleman FJ, Phan TTT, van den Hoogen FJA, Kaanders JHAM, Merkx MAW et al. The efficacy of hyperbaric oxygen therapy related to the clinical stage of osteoradionecrosis of the mandible. International journal of oral and maxillofacial surgery. 2017;volume 46(4):428-433.
  16. Niezgoda JA, Serena TE, Carter MJ et al. Outcomes of Radiation Injuries Using Hyperbaric Oxygen Therapy: An Observational Cohort Study. Advances in skin & wound care. 2016;volume 29(1):12-19.
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