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Soft Tissue Radiation Injury

Soft Tissue Radiation Injury

Soft Tissue Radiation Injury

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 Soft Tissue Radiation Injury (STRI). 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 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

(SKIN, PELVIC, BLADDER, RECTUM, COLON, CNS, LARYNX, BONY NECROSIS

BackgroundDelayed (also known as 'late' or 'chronic') effects of radiation are a complication of modern radiotherapy, which can be treated with HBO. Note that these chronic effects are to normal tissues that are juxtaposed to tumor tissue. Some examples of delayed radiation effects include soft tissue radionecrosis (Figures 1-3), radiation cystitis, radiation proctitis (Figure 4), and laryngeal chondroradionecrosis. The basic pathophysiology of delayed radiation tissue damage is endarteritis with resultant tissue hypoxia and secondary fibrosis. 
Goals of HBOT

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

    Diagnosis

    • Delayed radiation complications often manifest as non-healing wounds in previously irradiated areas. the wounds can be precipitated by an external insult such as surgery or trauma, even minor trauma. Some of these wounds are visible and some are not (e.g., radiation cystitis, vaginitis, proctitis, and urethritis)
    • It is important to differentiate delayed radiation injuries from acute radiation injuries, which usually resolve within a few weeks to a few months from radiation exposure and are treated symptomatically.

    Hyperbaric Criteria

    • Non-healing wound on irradiated area with onset at least six months since last radiation exposure  
    • History of radiation treatment (usually in excess of 40 Gray or 4,000 cGy) to the region of the documented injury
    • Wound that is non-responsive to conservative standard treatment 

    Evaluation 

    • Comprehensive history, to include:
      • Date cancer diagnosed
      • Date radionecrosis diagnosed
      • Type of radiation source. Total dose over total number of treatments. Radiation fraction administered (e.g., "Thirty treatments of electron beam radiation to the prostate gland in 200 cGy fractions for a total of 6,000 cGy. The prostatic urethra remained in field and has been affected."
      • Radiation date span
      • Previous treatment or therapies
    • Obtain the radiation-oncology reports  
    • Physical examination
    • Labs to order or review:
      • Complete Blood Count (CBC)
      • Serum Albumin
      • Pre-albumin
      • Erythrocyte Sedimentation Rate (ESR)
      • C-reactive protein (CRP)
    • Wound photographs (if possible)
    • Chest x-ray (provider discretion)
    • Electrocardiogram (ECG) (provider discretion)
    • Determine present oncological status (e.g., remission, local recurrence, metastasis, etc.)
    • Evaluation of tympanic membranes pre- and post-treatment as needed
    • Baseline visual acuity assessment
    • Smoking/nicotine cessation
    • Nutritional screening

    Treatment

    For cystitis or proctitis
    • 2.0-2.5  ATA oxygen for 90 minutes of oxygen breathing (Table 1 or 3)
    • Daily basis for 40 treatments 
    • Referring physician examines the area under direct visualization after 40 treatments and together with the HBO physician decides if to continue to 60. [2] [3]
    • Further treatments, in 20 treatment increments, will be determined by that examination and in consultation with the referring physician.
    • Rarely are 60 treatments exceeded. (Requires utilization review

    For open wounds in an irradiated field

    • 2.0-2.5  ATA oxygen for 90 minutes of oxygen breathing (Table 1 or 3)
    • Daily basis for 20-40 treatments
    • 20 treatments are prescribed prior to any surgical procedure. If the surgical procedure is complex, then we prefer 30 treatments prior to surgery.
    • After the operative procedure, the patient should receive 10 additional treatments (for a total of 30 or 40 treatments)
    • Extensions to treatment as described above.
    • Transcutaneous oximetry (TCOM) to determine tissue oxygenation after 20 treatments. This is an indirect measure of increased vascular density
      • After 20 treatments, If measurable signs of healing are present and periwound TCOM values reach 40 mm Hg, HBOT may be paused and the wound should be followed for continued healing. 
    •  If measurable signs of healing are not present after the initial 20 treatments re-evaluate looking for an incorrect diagnosis, persistent/recurrent tumor, persistent smoking, or other confounding problems. 
    • Wound evaluation and photography weekly and as needed
    • Evaluation of tympanic membranes pre- and/or post- HBOT as needed
    • Smoking cessation is highly encouraged.

    Follow-Up

    Treatment Threshold

    20 – 40 treatments; 60 treatments in rare cases. (Utilization review should be requested after 60 treatments.)

    Coding

    Refer to the ICD-10 Guideline for the appropriate ICD-10 Code

    Comments

    • If diabetes present, blood glucose should be checked within an hour prior to treatment and immediately post-HBOT by unit personnel. 
    • If petroleum based dressings and ointments are a necessary part of the surgical dressing, ensure that they are not exposed and are completely covered with a moistened 100% cotton airtight dressing.

    Primary Sources: Whelan and Kindwall [4], Weaver [5] [6]

    Fig.1. Soft tissue radionecrosis. 55 year old patient status post radical debulking surgery due to malignant nerve sheath tumor on left anterior thigh, 6600 cGy of external beam radiation, with non-healing wound 8 months after debulking. By Worth E.R M.D

    Fig.2. Soft tissue radionecrosis. Patient underwent HBOT for 2 months (30 sessions).  By Worth E.R M.D

    Fig. 3. Soft tissue radionecrosis. After initial 30 sessions of HBOT, patient underwent surgical wound coverage with vertical rectus flap, then 10 additional HBOT sessions.  By Worth E.R M.D

    Fig. 4. Radiation proctitis. Top: pre-HBOT, with friable mucosa visible on the lower left. Bottom: post-HBOT (40 sessions), friable mucosa is absent.  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. These wounds often fail conservative wound management and/or surgical management. The role of hyperbaric oxygen is one of overcoming a hypovascular - hypocellular - hypoxic tissue bed and the late-radiation effects. Acute inflammatory responses to ongoing or recently completed radiation therapy need to be differentiated. The HBOT mechanism of action in soft tissue radiation injury (STRI) is by stimulating angiogenesis, thereby overcoming the 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:

    History and Physical

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

    Physical Exam

    • Non-responding wound/ulcer within the previously irradiated field. We encourage you to be descriptive (e.g., "The non-healing breast wound is within the radiation tattoo marks on the lateral chest wall, and is located where the radiation oncologist noted peak radiation boost fields.")
    • Often, the patients will have a 'radiation tattoo' mark near the wound/ulcer. Photograph the wound/ulcer and make reference to the demarcation by way of the tattoo.
    • Use of HBOT often occurs in these cases by way of preparation for definitive coverage, whether flap or graft.
    • There may be cases where a flap has been attempted and failed due to the hypoxic nature of tissue in the irradiated field. Describe the surgical procedure and denote a timeline of flap/graft failure after that surgery.

    Impression

    1. Code First: Group 1 - Late Effects Radiation See ICD-10 Coding for STRN
    2. Group 2 - Anatomical Specific Radiation Codes See ICD-10 Coding for STRN


    Plan


    "For preventing wound healing complications in heavily irradiated tissue areas, we treat patients with 20 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. Should the patient already have a wound, 30 treatments are prescribed prior to any surgical procedure. We then treat 10 or more times postoperatively. For radiation cystitis/proctitis, we treat 30 times then have the referring physician examine the area under direct visualization. Further treatments, in 10 treatment increments, will be determined by that examination." enabled copy

    Additional comments to conclude the consultation may include: 

     “This patient has chronic radiation tissue injury consistent with delayed effects of ionizing radiation. This condition will be treated with hyperbaric oxygen therapy in conjunction with appropriate surgical repair or intervention.”

    Risk and Benefit of Hyperbaric Oxygen Treatment

    Indication for Hyperbaric Oxygen (HBO) Therapy 

    "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 has led to successful use of hyperbaric oxygen in other body areas affected by radiation. 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." enabled copy


    Sample Order


    CLINICAL EVIDENCE AND RECOMMENDATIONS  

    • 1A
       For patients with refractory radiation proctitis with a history of radiation treatment terminating at least 6 months prior to onset of signs and symptoms, we recommend HBOT as an adjunctive therapy to improve healing responses (as demonstrated by SOMA-Lent scores) (Grade 1A)
    • 1B
      For patients who need reconstructive soft tissue surgery or flaps into a previously irradiated area in the head or neck, we recommend HBOT therapy to prevent postoperative wound dehiscence (Grade 1B)
    • 2C
      For patients with hemorrhagic radiation cystitis with a history of radiation treatment terminating at least 6 months prior to onset of signs and symptoms, we suggest HBOT as an adjunctive therapy to resolve bleeding (Grade 2C) 
    • 2C
      For patients with radio-induced lesions of the larynx with a history of radiation treatment terminating at least 6 months prior to onset of signs and symptoms, we suggest HBOT as an adjunctive therapy to promote healing of the radio-induced lesions (Grade 2C). 
      • Rationale: The impact of HBOT in terms of its beneficial effects is likely to involve all three of these mechanisms in irradiated tissues: HBOT stimulates angiogenesis and secondarily improves tissue oxygenation; reduces fibrosis; and mobilizes and induces an increase of stem cells within irradiated tissues. [7][8] Quality of evidence varies according to the type of irradiated soft tissue being treated. Of note, high-certainty evidence derived from a well-designed randomized clinical trial supports the use of HBO to treat radiation proctitis [9] ; and moderate-certainty evidence supports the use of HBOT pre- and postoperatively to prevent wound dehiscence following head and neck soft tissue reconstruction in previously irradiated areas [10] . Evidence supporting use of HBO to treat hemorrhagic cystitis and radio-induced lesions of the larynx is of low-certainty, mainly supported by observational studies. [8]
      • Despite potential benefits, a frequent concern is the fear that HBO will somehow accelerate malignant growth or cause a dormant malignancy to be reactivated. However, an overwhelming majority of both clinical reports and animal studies showed no enhancement of cancer growth. [8] The patient should be informed of the possible risks and complications of hyperbaric oxygen therapy. The standard risks and benefits for HBOT have been discussed and listed here. 
      • Medicare coverage: Medicare covers preoperative and postoperative use of HBOT as an adjunctive therapy for existing soft tissue radionecrosis. 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.[11][12]  See section on 'Coverage and Reimbursement' below.

    CODING

    COVERAGE AND REIMBURSEMENT

    • Medicare covers preoperative and postoperative use of HBOT as an adjunctive therapy for existing soft tissue radionecrosis. 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.[11][12] 
    • Numerous forms of soft tissue radiation necrosis and treatment with HBOT have been documented with beneficial effect. Tissues previously irradiated with subsequent planned surgery appear to benefit from HBOT surrounding the surgery with decreased morbidity from large vessel necrosis. For this reason patients manifesting signs and symptoms of radiation injury will be approved for coincidental HBOT, without the histologic diagnosis of ongoing osteoradionecrosis or soft tissue radionecrosis.[13] 
    • Regarding Radiation Proctitis, a recent article on the UHMS website entitled UHMS Member Alerts the Society on Problems with CMS Coverage of Radiation Proctitis:  "The Case of the Disappearing Indication" written by Tom Bozzuto, DO, FACEP, FFACHM, UHM addresses an Ask the Contractor Teleconference (ACT) with Palmetto GBA. Dr. Leland Garrett, Medical Director of Palmetto GBA, Columbia South Carolina stated that radiation proctitis is not a covered indication under Soft tissue radiation injury as the bowel is not considered soft tissue. The only provider option available to have these claims reconsidered for payment would be the Medicare appeal process. It is imperative that providers are knowledgeable of their Local Coverage Determinations for hyperbaric oxygen therapy before proceeding with treatment.[14]
    • Utilization Review should be accomplished after 60 treatments when HBOT is applied to the treatment of radiation injury. Characteristically, most treatment courses for radiation injury will be in the range of 30-60 treatments when the course of treatment is carried out with daily treatments at 2-2.5 ATA of 100% oxygen for 90-120 minutes. [8] 
      • One caveat exists regarding the type of radiation used to treat certain cancers. We are aware of several institutions using neutron beams rather than the more common electron beam radiotherapy. Neutrons are heavy particles in comparison and have a surprisingly larger soft tissue radiation injury. Because of the particle size and collateral damage, these patients may require more than 60 treatments before wounds heal. We have seen this in several cases of head/neck and prostate radiation. 

    APPENDIX

    Summary of Evidence

    We reviewed the guidelines and studies published since guidelines were last updated. Applying the GRADE framework to the combined body of evidence, we found that the use of HBOT to:

    • Treat patients with hemorrhagic radiation cystitis is supported by low-certainty evidence (evidence level C) derived from observational studies and case series [8]
    • Prevent postoperative wound dehiscence in patients who undergo soft tissue reconstruction in the head and neck area after radiation, is supported by moderate-certainty evidence derived from a 2016 Cochrane meta-analysis [10]
    • Treat patients with refractory radiation proctitis (as demonstrated by improvement in SOMA-Lent scores) is supported by high-certainty evidence derived from a large RCT at low risk of bias conducted by Clarke et al.  [9]
    • Treat patients with radiation-induced lesions of the larynx is supported by low-certainty evidence derived from observational studies and case series  [8]
    • A large, retrospective review in Australia showed response for STRI and HBOT of 95% (proctitis), 85% (cystitis), and 84% (other body soft tissues). The HBOT complication rate was 10.6% (ear barotrauma), 4.2% (reversible myopia), 0.5% (dental barotrauma), and 0.5% (myocardial infarction) from 276 consecutive patients. [15] 

    Systematic reviews:

    • A 2016 systematic review [16] included 8 studies (1 uncontrolled observational cohort, 5 case series, and 2 case reports) including 720 participants who received HBOT for radiation induced skin necrosis.  [17] [18] [19] [20] [21] [22] [23] [24] Sites of skin necrosis included lower extremity, buttocks , scrotum, abdomen, chest wall, upper extremity, and head and neck. Majority of studies were at high risk of bias. Six studies provided the primary outcome measure of interest: complete wound healing after HBOT (98 patients). Pooled together the rate of complete wound healing was 79.6% (78/98). Two studies provided the secondary outcome measures of interest, symptomatic improvement of skin necrosis after HBOT (622 patients). Pooled together the rate of symptomatic improvement was 86% (535/622). Further analysis revealed the rate of complete resolution of pain symptoms was 30% (187/6 22), wound healing symptoms 30% (187/622), and wound drainage symptoms 39%(243/ 622). Evidence level is considered as low certainty (evidence level C) as currently no randomized control trial has tested the efficacy of HBOT in the treatment of skin necrosis due to late radiation tissue injury. Authors concluded that HBO is a safe intervention with promising outcomes, however additional evidence is needed to endorse its application as a relevant therapy in the treatment of radiation induced skin necrosis. 
    • A 2016 Cochrane systematic review [10] included 14 trials (753 participants) that assessed the effect of HBO on complete mucosal cover in people with osteoradionecrosis and on wound healing of dehiscence following complex head and neck surgery and irradiation. 2 RCTs (264 participants) assessed soft tissue radiation injuries and showed that HBO is effective in promoting healing of dehiscence following complex head and neck surgery and irradiation (moderate quality evidence, RR 4.23 95% CI, (1.06 to 16.83) of from single studies there was a significantly increased chance of improvement or cure following HBO for radiation proctitis (RR 1.72; 95% CI 1.0 to 2.9, P value = 0.04, NNTB 5). Authors concluded that these small trials suggest that for people with LRTI affecting tissues of the head, neck, anus and rectum, HBOT is associated with improved outcome.

    Guidelines:

    • The 2014 UHMS HBO Therapy Indications Book (Guidelines) and the 2017 European Committee for Hyperbaric Medicine Guidelines support the use of HBOT as therapy to treat Soft Tissue Radiation Necrosis, and although the guidelines use different evidence grading methodologies, they are in agreement regarding strength of recommendation.  [8]  [25] See table below:

    HBO therapy for Soft Tissue Injury

    UHMS, 2014

    ECHMG, 2017

    Treatment of soft tissue injury

    AHA Level Ib 

    n/a

    Treatment of hemorrhagic radiation cystitis 

    n/a

    Grade 1B

    Treatment of radiation proctitis

    n/a

    Grade 1A

    The treatment of soft-tissue radionecrosis (other than cystitis and proctitis), in particular in the head and neck area

    n/a

    Grade 2C

    Treating or preventing radio-induced lesions of the larynx 

    n/a

    Grade 3C

    Randomized Clinical Trials

    • In 2008, Clarke et al conducted an RCT with 120 evaluated participants that compared the effects of HBO on the late effects normal tissue-subjective, objective, management, analytic (SOMA-LENT) score and standardized clinical assessment in patients with chronic refractory radiation proctitis [9]. In the experimental group, the mean was lower (p = 0.0150) and the amount of improvement nearly twice as great (5.00 vs. 2.61, p = 0.0019). Similarly, Group 1 had a greater portion of responders per clinical assessment than did Group 2 (88.9% vs. 62.5%, respectively; p = 0.0009). Significance improved when the data were analyzed from an intention to treat perspective (p = 0.0006). Authors concluded that hyperbaric oxygen therapy significantly improved the healing responses in patients with refractory radiation proctitis, generating an absolute risk reduction of 32% (number needed to treat of 3) between the groups after the initial allocation. The study is considered by the 2016 Cochrane systematic review [10] as at low risk of bias (evidence level A). 

    Observational Studies

    • Case series support use of HBO to resolve hemorrhagic radiation cystitis  [8] (level C)

    REVISION UPDATES

    DateDescription
    4/15/19Added section on Coverage and Reimbursement
    5/21/19Added figures


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    REFERENCES

    1. CMS. National Coverage Determination (NCD) for Hyperbaric Oxygen Therapy (20.29) . 2017;.
    2. Harry T. Whelan, Eric Kindwall et al. Hyperbaric Medicine Practice 4th Edition Best Publishing Company. 2017;volume fourth():.
    3. Weaver L . "Hyperbaric Oxygen Therapy Indications” Best Publishing Company, North Palm Beach, FL . 2014;volume 469(13th Edition,):.
    4. 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;.
    5. Feldmeier JJ. Hyperbaric oxygen therapy and delayed radiation injuries (soft tissue and bony necrosis): 2012 update. Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, In.... 2012;volume 39(6):1121-39.
    6. Undersea and Hyperbaric Medical Society Hyperbaric Oxygen Committee,, et al. Hyperbaric Oxygen Therapy Indications . 2014;.
    7. Clarke RE, Tenorio LM, Hussey JR, Toklu AS, Cone DL, Hinojosa JG, Desai SP, Dominguez Parra L, Rodrigues SD, Long RJ, Walker MB et al. Hyperbaric oxygen treatment of chronic refractory radiation proctitis: a randomized and controlled double-blind crossover trial with long-term follow-up. International journal of radiation oncology, biology, physics. 2008;volume 72(1):134-143.
    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. Novitas Solutions, Inc et al. Local Coverage Determination for Hyperbaric Oxygen (HBO) Therapy (L35021) . 2015;.
    10. Thomas M. Bozzuto, DO, FACEP, FFACHM, UHM et al. Undersea and Hyperbaric Medical Society News and Announcements .;.
    11. Borab Z, Mirmanesh MD, Gantz M, Cusano A, Pu LL et al. Systematic review of hyperbaric oxygen therapy for the treatment of radiation-induced skin necrosis. Journal of plastic, reconstructive & aesthetic surgery : JPRAS. 2017;volume 70(4):529-538.
    12. Bui QC, Lieber M, Withers HR, Corson K, van Rijnsoever M, Elsaleh H et al. The efficacy of hyperbaric oxygen therapy in the treatment of radiation-induced late side effects. International journal of radiation oncology, biology, physics. 2004;volume 60(3):871-8.
    13. Feldmeier JJ, Heimbach RD, Davolt DA, Court WS, Stegmann BJ, Sheffield PJ et al. Hyperbaric oxygen as an adjunctive treatment for delayed radiation injury of the chest wall: a retrospective review of twenty-three cases. Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, In.... 1995;volume 22(4):383-93.
    14. Feldmeier JJ, Heimbach RD, Davolt DA, Court WS, Stegmann BJ, Sheffield PJ et al. Hyperbaric oxygen an adjunctive treatment for delayed radiation injuries of the abdomen and pelvis. Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, In.... 1996;volume 23(4):205-13.
    15. Feldmeier JJ, Heimbach RD, Davolt DA, McDonough MJ, Stegmann BJ, Sheffield PJ et al. Hyperbaric oxygen in the treatment of delayed radiation injuries of the extremities. Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, In.... 2000;volume 27(1):15-9.
    16. Hampson NB, Holm JR, Wreford-Brown CE, Feldmeier J et al. Prospective assessment of outcomes in 411 patients treated with hyperbaric oxygen for chronic radiation tissue injury. Cancer. 2012;volume 118(15):3860-8.
    17. Korpinar S, Cimsit M, Cimsit B, Bugra D, Buyukbabani N et al. Adjunctive hyperbaric oxygen therapy in radiation-induced non-healing wound. The Journal of dermatology. 2006;volume 33(7):496-7.
    18. 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.
    19. Uzun G, Candas F, Mutluoglu M, Ay H et al. Successful treatment of soft tissue radionecrosis injury with hyperbaric oxygen therapy. BMJ case reports. 2013;volume 2013():.
    20. 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.
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