UHM 2002, Vol.29, No.1 - Literature review of HBO and delayed radiation injuries
A systematic review of the literature reporting the application of hyperbaric oxygen prevention and treatment of delayed radiation injuries: An evidence based approach
].]. FELDMEIERand N. B. HAMPSON
Radiation Oncology Department, Medical College of Ohio; Toledo, Ohio; and Center for Hyperbaric Medicine, Virginia Mason Medical Center, Seattle Washington
Feldmeier 11, Hampson, NB. A systematic review of the literature reporting the application of hyperbaric oxygen prevention and treatment of delayed radiation injuries: An evidence based approach. Undersea Hyper Med 2002, 29(1) :4-30. The treatment of delayed radiation injuries (soft tissue and bony radiation necrosis) is one of thirteen conditions approved by the Hyperbaric Oxygen Therapy Committee of the Undersea and Hyperbaric Medical Society as appropriate indications for hyperbaric oxygen (HBOz). This paper provides a systematic review of the literature reporting the results of HEOz therapy in the treatment and/or prophylaxis of delayed radiation injury. Since the introduction of the concept of evidence based medicine, the medical community in general has set out to apply more critical and stringent standards in evaluating published support for therapeutic interventions. Evidence based medicine is designed to discover the best evidence available and apply it in daily practice for treatment of the individual patient. The preferred level of evidence is the randomized controlled trial, however, other evidence has merit as well. In this review, seventy-four publications are represented reporting results of applying HEOz in the treatment or prevention of radiation injuries. These are appraised in an evidence-based fashion by applying three established systems of evaluation. All but seven of these publications report a positiye result when HEOz is delivered as treatment for'or prevention of delayed radiation iIUury. These results are particularly impressive in the context of alterhative interventions. Without HBOz, treatment often requires radical surgical intervention, which is likely to result in complications. Other alternatives including drug therapies are rarely reported, and for the most part have not been the subject of randomized controlled trials. Based on this review, HEOz is recommended for delayed radiation injuries for soft tissue and bony injuries of most sites. Of note, an increasing body of evidence supports HEOz for radiation-induced necrosis of the brain. For other radiation-induced neurological injuries, additional study is required before recommendations for routine hyperbaric therapy can be made.
Leave this space for key words which the authors haven't put in.
hyperbaric oxygen, radiation injwy, complications of cancer treatment, systematic renew
Introduction:
. Approximately 1.2 million new cases of invasive cancer will be diagnosed this year in the United States and approximately one half of these patients will receive radiation therapy as part of the management of their malignancy.! About one half of patients treated for cancer become long term survivors. Serious radiation complications are rare but occur in up to 5% of those patients receiving therapeutic radiation.2These complications characteristically occur after a latent period that varies from several months to several years. The etiology of delayed radiation injwy is not fully understood though most would agree that endarteritis, tissue hypoxia and fibrosis are consistellt fmdings and are certainly major contributors to pathogenesis.2 Historically, conservative management of delayed radiation iryuries including frank radionecrosis has been unsatisfactory. Radiation injuries may be life-
Copyright @ 2002 Undersea and Hyperbaric Medical Society, /nc 4

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UHM 2002, Vol. 29, No.1 - Literature Review for HBO and radiation injuries
threatening and may significantly reduce quality of life under certain circumstances. Definitive treatment may require surgical resection or bypass of the affected part. In a patient who has in many cases already survived aggressive therapy including chemotherapy and surgery in addition to radiation, the prospect of further radical treatment possibly including a major surgical intervention is most unwelcome. Additionally surgical intervention in a heavily radiated field may result in delayed wound healing, dehiscience or infection. These post -operative complications may be life threatening in severity.
Mandibular radiation necrosis has been treated with hyperbaric oxygen for some time with consistently positive results. Hyperbaric oxygen therapy is applied now with increasing frequency to radiation injuries and necrosis of other tissues and at other anatomic sites. It is felt to be effective by enhancing angiogenesis and in so doing, providing oxygen to meet the metabolic demands of radiation impaired tissues.
This paper reviews and critically assesses the literature in radiation injury as one of 13 indications approved as appropriate for therapeutic intervention with hyperbaric oxygen by the Undersea and Hyperbaric Medical Society.3 It summarizes the published literature reporting use of hyperbaric oxygen (HB02) in the comprehensive treatment, or prophylaxis of delayed radiation injury. A major limitation in this effort is the paucity of randomized controlled clinical trials available to support or refute this intervention. Although randomized controlled trials are indeed the gold standard for establishing the efficacy of a therapeutic intervention, other evidence including pre-clinical studies and retrospective case series have merit. 4 The literature presented herein is evaluated using three previously published review schemes designed to critically assess the strength of literature in support
of employin? a therapeutic intervention. The first of these has been developed by the American Heart
Association. ,5 The second is the system developed and utilized by the National Cancer Institute's PDQ Editorial Board in their presentation of ongoing reviews of cancer treatment information.6 The third is an adaptation of the approach developed by the BM] Publishing Group and used in the publication, Clinical Evidence.7
Three Models for literature Assessment:

In 1995, the American Heart Association (AHA) published a scheme to evaluate and subsequently to recommend to the Federal Drug Administration (FDA) and to the Health Care Finance Administration or HCFA (now CMS) the value of therapeutic interventions.4 In 1998, the AHA updated and further defmed and clarified this system.5. Table 1 specifies levels of evidence as defmed and applied by this system to interventions. Randomized controlled trials are given the most weight and historical acceptance given the lowest weight. Human case series and animal studies are given intermediate weighting.
Table 1.
AHA Emergency Cardiovascular Care Levels of Evidence Level 1: Statistically significant randomized controlled trials (RCT's).
lA: IB:
Meta-analysis of multiple positive RCT's.
One or more positive RCT's with statistically positive results
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UHM 2002, Vol. 29, No.1 - Literature Review for HBO and radiation injuries
IC:
Meta-analysis with inconsistent but significant results
Level 2: Statistically insignificant RCT's
,j
1.\
i'(
2A: 2B:
Meta-analysis of positive RCI's but not statistically significant 
One or more positive RCI's; not statistically significant
2C:
Meta-analysis of inconsistent RCI's; not statistically
 
Level 3: Prospective, controlled, but not randomized cohort studi Level 4: Historic, non-randomized cohort or case-control studies
Level 5: Human case series
Level6: Animal or mechanical model studies
Level7: Reasonable extrapolations from existing data; quasi-experimental designs LevelS: Rational conjecture (common sense); historical acceptance as standard practice
Table 2 demonstrates the principles of the AHA system as applied to specific therapeutic interventions and as related to assessing the evidentiary support for such interventions.
Table 2.
The American Heart Association System
Class I: Definitely Recommended. Excellent evidence provides support.
Class IT: Acceptable and Useful.
IIa: Vel)' good evidence provides support.
lIb: Fair-to-good evidence provides support.
'"
Class III: Not Acceptable, Not Useful, May be Harmful.
lndetenninate: A Continuing Area of Research; no recommendation until further
	research is available.
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UHM 2002, VoL 29, No.1 - Literature Review for HBO and radiation injuries
After a review of the published evidence for a particular therapy, the AHA system assigns interventions into categories according to the strength of the evidence supporting their use. Interventions designated as Category I, lla or llb are recommended for application to clinical practice while category III interventions are not supported. Therapeutic interventions assigned to the "Indeterminate Category" are judged to require additional investigation prior to recommendation for or against their application.
The National Cancer Institute (NCI) provides Physicians' Data Query (PDQ) as an Intemetaccessible summary of current treatment and diagnostic standards for the diagnosis and therapeutic management of common childhood and adult malignancies. Through the NCI, summaries are available to the clinician, and separate summaries are available to the layperson written in appropriate language and level for comprehension by an inquiring patient or family member. Recently, the PDQ Editorial Board has begun to include assessments of the level of supporting evidence for a particular intervention utilizing their own quantitative system (summarized in Table 3).
Table 3.
National Cancer Institute: Physicians Data Query (PDQ) Level of Evidence
1. Evidence Supported by Randomized Controlled Trials (RCT) Ii is a Double Blinded RCT
Iii is an RCT that is not blinded
2. Evidence Supported by Controlled but Non-Randomized Trials
	(e.g. allocation to a given group is detennined by birth date or day of week enrolled)
3. Evidence is Supported by Case Studies
3i is a case series that is population based and consecutive
3ii is a case series which is consecutive but not population based
3iii is a case series which is neither population based nor consecutive
This system is a two-tiered system. The first or numeric portion is assigned in the following fashion:
Level 1 represents evidence supported by a randomized controlled trial(s) (RCT). This numeric grade is further modified so that Ii represents a double-blinded study and Iii represents an RCT that is not blinded. Meta-analyses of RCT's are given level I status with the suffIx modifier applied in the same fashion in regard to blinding as a single RCT.

Level 2 represents non-randomized but controlled clinical trials. This group would include trials in which the allocation of a patient to the treatment or control group is set by birth date, day of clinic appointment, bed availability or any other determinant, which would make allocation known to the investigator prior to obtaining informed consent.
Level 3 are case series. Category 3i is a series, which is consecutive and population based. Category 3ii is a case series reporting consecutive but not population based cases. Category 3ill reports cases which are neither consecutive nor population based.
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UHM 2002, VoL 29, No.1 - Literature Review for HBO and radiation injuries
The PDQ grading system includes a secondary component based on the "strength of the end points." For Category A, the end point is total mortality. For Category B, the end point is disease specific mortality. Category C represents quality of life outcome measures and Category D reports other surrogate measures of outcome such as disease-free survival and tumor response rate. This second set of categorizations of PDQ evidence is more or less specific to cancer treatment and will not be applied strictly in reviewing the evidence available for hyperbaric oxygen for radiation injuries. However, it is noted that unresolved serious delayed radiation injuries cause death under certain circumstances and certainly decrease quality of life in most circumstances.
The PDQ system evaluates individual papers in. regard to the strength of evidence but does not numerically sum the evidence in a formal fashion to assign an overall assessment of the strength of the evidence for any particular therapeutic modality in a given circumstance.
In Clinical Evidence, the editors seek to provide the practicing clinician with a handy reference providing evidence-based reviews of interventions for common conditions seen in primary care and hospital practice. This publication, which is updated every six months, begins each section by asking a question about available therapies for a particular clinical problem. For example, in the section on metastatic breast cancer, a question asked is "what are the effects of treatment for bone metastases". Then, individual therapies are discussed in terms of "Benefits", "Harms" and "Comments."
The "Benefits" sections first presents published evidence from systematic reviews and randomized controlled trials. These are the preferred levels of evidence. If randomized controlled trials are not available for a given question, other published evidence supporting a therapeutic strategy is presented and discussed to develop arguments supporting that intervention. A discussion of potential complications and side effects follows and is included in "Harms" so that the adverse effects can be compared to the evidence in favor of therapy, and decision making based on risk to benefit considerations can be made by the clinician.
"Comments" present additional considerations, amplifying or modifying information to clarify further the application of a particular therapy in relevant circumstances.
As we apply the "Clinical Evidence" approach to hyperbaric oxygen for radiation injuries, the
recent reports of Platki et als and Sheffield and Desautels are considered in regard to "Harms". Both of these publications demonstrate the hyperbaric oxygen therapy is. a very safe modality and unlikely to be accompanied by significant morbidity if delivered appropriately. For this particular application, concern has been voiced that hyperbaric oxygen may increase the likelihood of recurrent cancer. A review by Feldmeier et al10  in 1994 failed to uncover evidence of increased risk of cancer recurrence or progression for patients treated for radiation injuries. In applying the "Clinical Evidence" approach to review each of the individual anatomic sites or tissues involved by injury, we are asking the question, "Is hyperbaric oxygen effective in resolving or palliating this disorder?"
The BMJ scheme assigns a verbal description of the strength of support for a particular modality in a given circumstance based on a compilation of all evidence available in that particular circumstance. To illustrate these principles in Tables 4 through 11, we have modified the system slightly to assign a verbal description of the strength of the evidence for each paper. We then combine these to give an overall strength for a particular indication within the discussion  portion for each indication.

Application of Oxygen Intervention for Radiation Injury: Site Specific Summaries: To discuss the application of evidence-based models to radiation injury, we will follow the discussion site by site in the same order as used in Tables 4 through 12. For ease in reading the Table, negative studies are entered in bold italics and the author's name underlined. Single
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UHM 2002, Vol. 29, No.1 - Literature Review for HBO and radiation injuries
case reports are considered a case series of "one" for classification and entry into Tables 4 through 12. Papers discussing the application of hyperbaric oxygen to the treatment or prevention of the various radiation injuries were sought by searching several Internet accessible databases including "Pubmed" and "Cancerlit". Once a paper was found, its references were manually reviewed to search out additional appropriate references. Previous proceedings of the annual meeting of the Undersea and Hyperbaric Medical Society and meetings of the International Congress of Hyperbaric Medicine were searched manually.
L
Prophylaxis of Mandibular Osteoradionecrosis
Table 4 summarizes literature in which hyperbaric oxygen has been applied to the prevention of mandibular osteoradionecrosis (ORN). Robert E. Marx, D.D.S. has published a randomized controlled trial reporting the successful use of hyperbaric oxygen in preventing mandibular radiation necrosis by giving hyperbaric oxygen before and after dental extractions. This report provides us with AHA and NCI level 1 evidence.l1 Two additional clinical series present their results in the prophylactic treatment of 53 additional patients (AHA level 4 or 5 and NCI level 3ii evidence). If we combine the patients from all three reports, we find an incidence of osteoradionecrosis (ORN) in 4.5% (4 of 90) in the HB02 prophylaxis group (2 of 37 Marx; 1 of 29 Vudiniabolal2; and 1 of 24 DavidI3). In Marx's control group, the incidence of osteoradionecrosis was 29.9% (11 of 37).
	The AHA therapeutic intervention classification for ORN prophylaxis merits a designation as a "Class Ia" indication for HB02.
	The BMJ Clinical Evidence review of this indication would be "Beneficial" based on the
randomized controlled trial and the low incidence of "Harms".
Table 4.
Published Reports of Hyperbaric Oxygen for Prevention of Mandibular Necrosis
Author
Type of Report
Clinical Evidence
Comments
Marx (1985)11	RCT -74 patients	1B	1ii	Beneficial	5.4% ORN in HBO Group	
					29.9% in non-HBO Group	
Vudiniabola	Case Series-37	4	3ii	Likely to be	1 of 29 HBO and 7 of 8 non-HBO	
(1999) 12	patients			Beneficial	developed ORN	
David (2001)13	Case Series-24	5	3ii	Likely to be	1 of 24 developed ORN	
	patients			Beneficial		
ll. Treatment of Existing Osteoradionecrosis of the Mandible:
	The literature for existing mandibular osteoradionecrosis (ORN) is summarized in Table 5. 13--26
A total of 14 publications are reviewed.
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UHM 2002, Vol. 29, No.1 - Literature Review for HBO and radiation nyunes
	Table 5.										
			'erbaric Ox	en as Treatment for Mandibular Necrosis							
				AHA Grade	NCI Grade	Clinical Evidence	Comments				
	Mainous	Case Series-14	5			3ii	Likely to beBeneficial	Relief of pain			
	(1975) 14	patients							and resolution of		
									sinus tracts in all		
									patients		
	Hart	Case Series-46	5			3ii	Likely to be Beneficial	37 of 46			
	(1976) 15	patients							Resolved		
	Farmer	Case Series-13	5			3ii	Likely to be Beneficial	Radiographic			
	(1978) 16	patients							Improvement in		
									10 of 13		
									patients		
	Tobey	RCT -12 patients	1B	1 ii	Beneficial	Significant					
	(1979) 17	100% 02 at 1.2 vs							improvement in		
		2.0 AT A							those at 2.0 vs		
									1.2 AT A		
	Davis	Case Series-23		5	3ii	Likely to be Beneficial	20 of 23				
	(1979) 18	patients							resolved -		
	Marx	Case Series-58		5	3ii	Likely to be Beneficial	100%				
	(1983) 19	patients							resolution with		
									HBO and		
									aggressive		
									surgery		
	Marx	Case Series-70				3ii	Likely to be Beneficial	100%			
	(1984)20	patients							resolution with		
									HBO and		
									aggressive		
									surgery		
	Mounsey	Case Series-41		5	3ii	Likely to be Beneficial 34 of 41 had					
	(1993)21	patients							significant		
									improvement		
	McKenzie	Case Series-26		5	3ii	Likely to be Beneficial 18 of 26					
	(1993)22	patients							pertsistent		
									mucosal and		
									epithelial		
I									healing		
	van	Case Series-29		5	3ii	Likely to be Beneficial 20 of 29					
	Merkester	patients							patients		
	n(1995t								resolved		
	Epstein 4	Case Series-20 -		5	3ii	Likely to be Beneficial	120f20				
		patients with long							resolved with		
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UHM 2002, Vol. 29, No.1 - Literature Review for HBO and radiation injuries
	term follow up				long term	
					followup	
Maier	Case	3	2	Not Beneficial	A negative	
(200015	Series-41				trial of	
	patients				hyperbaric	
					compared to	
					historic	
					controls; 13	
					of 20 HBD	
					resolved	
Curi	Case	5	3ii	Likely to be Beneficial	14 of 18	
(2000)26	Series-18				resolved	
	patients					
David	Case	5	3ii	Likely to be Beneficial	48 of 51	
(2001)13	Series-51				showed	
	patients				improvement	
One very small randomized controlled trial of 12 patients by Tobey et all7 is positive. These patients were randomized to 100% oxygen at 1.2 vs 2.0 ATA. The authors state that those patients treated at 2.0 AT A "experienced significant improvement" compared to the group receiving oxygen at 1.2 AT A. No details are given regarding randomization or outcome determination. In fact we cannot tell how many patients were assigned to each group. The study is randomized and doubly blinded in that neither the patient nor the clinician assessing the patient knew which therapy the patient was receiving. Even though it is a small study, it does present level 1 evidence. This study is therefore assessed an AHA IB and a NCI Iii level of evidence classification.
In addition to Tobey's trial, thirteen additional reports are listed in Table 5. All of these trials present AHA LevelS evidence and NCI Level 3ii evidence. Twelve of the 13 trials are positive. Only the report by Maier et al fails to show an advantage for hyperbaric oxygen in the treatment of existing ORN. In this paper, hyperbaric oxygen is given only after an attempt is made at surgical correction. No hyperbaric oxygen was given prior to surgery. Marx has previously established the important principle of pre-operative HBO prior to surgical wounding in irradiated tissues, which has been widely accepted for applying HBOz to the treatment ofORN.
Combining all of the reported cases in Table 5 (excluding those of Tobey and noting that Marx's second report includes the 58 patients reported earlier) provides a total of 371 cases of mandibular ORN. Improvement is reported in 310 cases or 83.6%. Although resolution would be a better endpoint, hyperbaric oxygen was not combined with aggressive extirpation of necrotic bone or with surgical reconstruction of bony discontinuity, especially in the earlier reports. M~l has reported the best results of any author and identified and emphasized the need for optimizing surgery and HBOz by the pre-surgical application of HBOz. Marx reports 100% success, but this includes mandibulectomy and reconstruction in 73% of his patients. Dr. Marx also sets high standards for successful intervention in those patients requiring mandibulectomy and reconstruction by requiring not only successful reestablishment of bony continuity but also functional success in supporting dentures for cosmesis and mastication.
Based on one small single RCT and consistent experience reported in case series, HBOz as treatment for ORN is probably an AHA class IIa indication (Acceptable and Useful Based on Very
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UHM 2002, Vol. 29, No.1 - Literature Review for HBO and radiation injuries
Good Evidence). Applying the BM] standards, the treatment of ORN by HB02 is "Likely to be Beneficial" once again recognizing the low likelihood of "Harms" and consistent reports of success.
ill. Treatment of Soft Tissue Radiation Necrosis of the Head and Neck Including Laryngeal Necrosis:
Table 6 includes 7 published reports of HB02 applied to soft tissue injuries of the head and neck.18, 27
32
Table 6.
Hyperbaric Oxygen as Treatment for Soft Tissue Radiation, Injury of the Head and Neck
Author
Type of Report
]AHA Grade I NCI Grade I
Clinical Evidence
Comments
	Davis (1979)19 Case Series-16	5	3ii	Likely to be Beneficial	15 of 16 resolved		
		patients					
	Ferguson	Case Series-8	5	3ii	Likely to be Beneficial	Dramatic improvement	
	(1987)27	. patients				in 7 of 8	
		with laryngeal					
		necrosis					
	Feldmeier	Case Series-9	5	3ii	Likely to be Beneficial	Resolution in all 9	
	(1993)28	patients				patients	
		with laryngeal					
		necrosis					
	Neovius	Case series of 15	4	3ii	Likely to be Beneficial	Healing in 12 of 15	
	(1997)29	patients compared to				patients; 2 improved; 1	
		historical				non-healing; compared	
		control group				to 7 of 15 healed in the	
						control group with 1	
						fatal bleed	
	Marx (1999)30	Prospective	3	2	Likely to be Beneficial	Statistically significant	
I		controlled but not				reduction in wound	
1		randomized study of				infection, dehiscience	
		160 patients				and delayed healing in	
						HBO group	
Filintisis
(2000)31
Case Series-18 patients
with laryngeal. necrosis
5
3ii
Likely to be Beneficial
13 of 18 had major improvement
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UHM 2002, Vol. 29. No.1 - Literature Review for HBO and radiation injuries
Naroznv
(2001)3:1
Case Series-2 patients soft tissue necrosis including larynx and pharynx
5
3ii
Likely to be Beneficial Resolution in both
	patients
In Hyperbaric Medicine Practice30, Marx reports his experience in a prospective controlled but not randomized study. Those patients who refused HBOz or for whom treatment was not practical due to distance from a chamber or other fmancial reasons were assigned to the control group. These cohorts of patients were treated concurrently and all other aspects of their treatment were identical. This study is therefore considered AHA level 3 and NCI level 2 evidence. In his report of 160 patients receiving hyperbaric oxygen in support of surgical resection or flap reconstruction in heavily irradiated patients comparing wound infection, wound dehiscence and delayed wound healing, Marx reports the incidence of complications in the HBOz group versus the control group in the following fashion: 1. Wound infection: 6% versus 24%; 2. Wound dehiscence: 11% versus 48%; and 3. Delayed wound healing: 11 % versus 55%. Applying the Chi square test to these results we obtain P values of 0.004, less than 0.0001 and less than 0.0001 respectively. These patients received 20 pre-operative HBO treatments followed by 10 post-operative treatments at 2.4 ATA.
In addition to the large controlled trial reported by Marx, six additional publications reporting case series are listed in Table 6. These consistently report a positive outcome in patients treated with HBO for soft tissue radionecrosis of the head and neck. A case series by Davis et al reports success in 15 of 16 patients treated for soft tissue radionecrosis of the head and neck. Many of these patients had large chronic soft tissue wounds as a result of their radiation injury. In 1997 Neoviusz9 and colleagues reported 15 patients treated with HBOz for wound complications within irradiated tissues. They compared this group to a historical control group from the same institution. Twelve of the 15 patients in the HBOz group healed completely with improvement in 2 and no benefit in 1. In the control group only 7 of 15 patients healed. Two patients in the control group developed life-threatening hemorrhage and 1 of them exsanguinated.
The effects of HBO on chondroradiation necrosis of the larynx are reported by 3 authors from 3 different institutions.Z7.Z8.31 The majority of these patients had severe (Chandler's Grade III or IV
necrosis). Most patients with severe laryngeal chondroradionecrosis will require laryngectomy.33-36 If the results from these 3 trials are combined, only 6 of 35 patients underwent laryngectomy The rest maintained their larynx and most had good voice quality after HBO.
Based on the Marx controlled trial and the consistent outcome in the reported case series, soft tissue radiation injury of the head and neck can be considered an AHA category lIb (acceptable and useful based on fair to good evidence). Applying the BM] system, the application of hyperbaric oxygen to soft tissue radiation injuries of the head and neck would be rated "likely to be beneficial" based again on the consistently positive outcome and low likelihood of substantial side effects or "harms".
IV. Treatment of Radiation Cystitis
	Table 7 lists 17 published reports detailing results of HBOz interventions in the treatment
hemorrhagic radiation induced cystitiS.37-53 These publications are all case series. The report by
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UHM 2002, Vol. 29, No.1 - Literature Review for REO and radiation injuries
Bevers46, which includes the largest number of patients, was a prospective but not a controlled trial. In the fmal report by Weiss et al48, the earlier patients reported by the same author were included. The second paper by Lee43 reporting 25 patients includes the 20 patients previously reported by the same author. If the patients in these 17 publications are combined, a total of 190 patients were treated with HBOz with 145 patients or 76.3% resolving with HBOz treatment.
			Table 7.					;}}	)q				
			Hyperbaric Oxygen as Treatment for Radiation Cystitis										
			Author	Type of Report		NCI Grade	Clinical Evidence	Comments					
			Weiss (1985)37 Case Series-3 patients	5	3ii	Likely to be Beneficial	3 of 3 resolved						
			Schoenrock	Single Case Report	5	3ii	Unknown Benefit	1 of 1 resolved					
			(1986)38										
			Weiss (1989)39 Case Series-8 patients			Single positive case							
				5	3ii	Likely to be Beneficial	7 of 8 resolved						
			Rkmans	Case Series-l 0 patients	5	3ii	Likely to be Beneficial	6 of 1 0 resolved					
			(1989)40										
			Norkool	Case Series-14 patients	5	3ii	Likely to be Beneficial	8 of 14 resolved					
			(1993)41										
			Lee (1994)42	Case Series-20 patients	5	3ii	Likely to be Beneficial	16 of 20 resolved					
			Lee(1994)43	Updated Case		5	3ii	Likely to be Beneficial	21 of 25 resolved				
	.			Series 25 patients									
I	I												
	I	Akiyama	Case Series-2 patients	5	3ii	Likely to be Beneficial	2 of 2 resolved						
			(1994)44										
			Weiss (1994)45 Case Series-13 patients	5	3ii	Likely to be Beneficial	12 of 13 resolved						
			Bevers(1995)46 Prospective non-		5	3ii	Likely to be Beneficial	37 of 40 resolved					
				randomized trial	of40								
				patients									
			Del Pizzo	Case-Series-11 patients	5	3ii	Not likely to be	3 of 11 resolved					
		t	{1998l7					Beneficial					
													
			Weiss	Case Series-29		5	3ii	Likely to be Beneficial	26 of 29 resolved;				
		1	(1998)48	patients							average flu 18.5		
		I									mos		
		I											
			Miyazato	Case Series-l 0 patients	5	3ii	Likely to be Beneficial	7 of 10 resolved					
			(1998)49										
			Suzuki	Case Series-3 patients	5	3ii	Likely to be Beneficial	3 of 3 resolved					
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UHM 2002, Vol. 29, No.1 - Literature Review for HBO and radiation injuries
(1998)50
Mathews
(1999)51
Case Series-17 patients
5
3ii	Likely to be Beneficial	11 of 17 resolved	
3ii	Likely to be Beneficial	6 of 8 resolved	
3ii	Likely to be Beneficial	14 of 20 resolved	
Mayer (2001 )52 Case Series-8 patients
5
Hendicks
(2000)53
Case Series-20 patients
5
Many patients reported in the HB02 experience had already failed conservative management including irrigation and instillation of alum or formalin. Severe hemorragic radiation cystitis is unquestionably a life threatening and quality of life limiting disorder. Cheng and F0054 have reported their experience in managing 9 serious refractory cases of hemorrhagic radiation cystitis without HB02. Six patients were treated with bilateral percutaneous nephrostomies. Three patients required
ileal loop diversions of their urinary stream. Four of nine (44%) patients ultimately died in spite of these aggressive treatments. Similarly, Sun and Cha055 reported 3.7% mortality due to bladder injury in their review of 378 patients treated with radiation for cervical cancer.
A success rate of 76.3% with HB02 is impressive when results with other more aggressive interventions are considered. It is also noteworthy that 16 of 17 publications listed in Table 3 are positive reports. Patients listed in Table 3 represent patients treated in several different countries on 3 different continents with consistent benefit seen in a large majority of patients in each study except that of Del pizZO.46
Although there are no randomized controlled trials supporting this indication for HB02, the results of the case series reviewed are so consistent that a Class IIa AHA designation (Acceptable and Useful) and a BM] designation of "Likely to be Beneficial" for radiation cystitis appears to be reasonable.
v. Treatment of Radiation Induced Chest WaD and Breast Injury
Four reports of HB02 treatment of chest wall and breast radiation injury are listed in Table 816.5658 These are considered AHA level 5 or NCI level3ii evidence with the exception of the publication of Carl54 which has a concurrent non-randomized control group and would therefore be considered an AHA level 4 study.
Table 8.
Hyperbaric Oxygen as Treatment for Radiation Injury of the Chest Wall and Breast
Author	IType of Report	I	AHA INCI Grade IClinical Evidence	I Comments
Grade
Hart
(1976)15
Case Series-6 patients
5
3ii
Likely to be Beneficial HB02 as adjunct to skin graft into irradiated bed
all 6 grafts successful
Feldmeier
(1995)56
Case Series-23 patients-8 soft
5
3ii
Likely to be Beneficial 6 of 8 soft tissue
	resolved
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UHM 2002, Vol. 29, No.1 - Literature Review for HBO and radiation injuries
'"
	tissue-15 bone+ soft		
	tissue necrosis of 9h€}st		
	wall		
Carl (1998)57	Case Report	5	
	Single positive		
	case		
Carl (2001)58	Case Series-44	4	
	patients 32 received		
	HBO;12 control		
8 of 15 soft tissue+bone resolved
3ii
No category for single case report
Resolution of breast edema and pain
2
Likely to be Beneficial
Statistically significant improvement in pain, erythema and edema of breast in HBO group compared to control
1"
In the fIrst series, Hart16 reports the use of HBOz as an adjunct to skin grafting with all patients experiencing graft take. In the second, Feldmeier5z reports 23 cases: eight with soft tissue only necrosis and 15 with a combination of bone and soft tissue necrosis. Resolution of soft tissue involvement only was 75%, while resolution in those with a component of bone necrosis was 53% and all required resection of necrotic bone.
In a case report Carl and Hartmann53 in 1998 published their results in treating a patient with long standing symptomatic breast edema following lumpectomy and irradiation. The patient received 15, 90 minute HBOz treatments at 2,4 AT A. The patient had complete resolution of pain and edema.
Carl and his associates54 in 200 I reported outcome in 44 patients who suffered complications after lumpectomy and irradiation for early breast cancers. These patients were found to have pain, edema, fIbrosis and telengectasias. Each patient experienced these complications in various combinations. The severity of symptoms was assessed a score for each patient based on a modifIed LENT -SOMA score. Only patients with at least grade 3 pain (persistent and intense) or a summed LENT -SOMA score of 8 were studied. Each patient was assessed a score from I to 4 in the severity of symptoms in the categories of pain, edema, fibrosis/ fat necrosis and telangectasia/erythema. Thirty-two patients agreed to undergo HBOz treatment while 12 women refused HBOz and constituted the control group. Women' who received HBOz had a statistically signifIcant reduction in post treatment SOMA-LENT scores compared to those who did not. Fibrosis and telangectasia were not reduced. Women in the control group continued to demonstrate symptoms at the completion of the trial with no improvement in pain or edema. Seven women in the HBOz group had complete resolution of their symptoms. , .
Based on the information a1)ove and delineated in Table 3, hyperbaric oxygen for radiation induced chest wall or breast injury would qualify as an AHA level IIB (Acceptable and Useful based on Fair to Good Evidence) inclication. In the BMJ scheme it would be considered "Likely to be BenefIcial."
~
VI. Treatment of Radiation Proctitis and Enteritis
Table 9 lists 14 publications reporting experience in applying hyperbaric oxygen as treatment for radiation enteritis and proctitis.59-71 The fIrst paper is a case report detailing the successful treatment of
a single patient with hemorrhagic proctitis.	'
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UHM 2002, Vol. 29, No.1 - Literature Review for HBO and radiation injuries
Table 9.
Author
Type of Report
NCI Grade
Clinical Evidence
Comments
Bouachour (1990)59	Case Series-8	5	3ii	Likely to be Beneficial	6 of 8 patients		
	patients					with	
						hemorrhagic	
						proctitis	
						resolved	
Charneau (1991)60	Single Case	5	3ii	Positive Case	Single patient with		
	Report					successful treatment	
						of hemorrhagic	
						proctitis	
Nakada (1993)61	Single Case	5	3ii	. Unknown Effectiveness Single patient with			
	Report			Single Positive Case	successful		
						treatment of	
						hemorrhagic	
						proctitis	
Feldmeier (1995)62	Animal Study	6	Not	Not Clinical but Positive Reduced			
			Clinical Study	Fibrosis and			
						reduced gross	
						appearance of	
						enteritis in	
						murine ileum	
Feldmeier (1996)63	Case Series-8	5	3ii	Likely to be Beneficial	4 on		
	patients:					proctitis/colitis	
	7 proctitis/colitis;					resolved; 1	
	1 enteritis					enteritis did not	
						resolve	
Woo (1997)64	Case Series-18	5	3ii	Likely to be Beneficial	2 patients		
	patients					had	
						complete	
						resolution;	
						8 partial	
						and no change in 8	
Warren (1997)65	Case Series-14	5	3ii	Likely to be	7 patients complete		
	patients			Beneficial	resolution; 2 improved 5		
					patients non-responders		
Bredfelt (1998)66	Case Series-19	5	3ii	Likely to be	Complete		
	patients			Beneficial	resolution in		
					47%; 37%		
					improved		
					16% non-		
					responders		
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UHM 2002, Vol. 29, No.1 - Literature Review for HBO and radiation injuries
	Feldmeier (1998)67	Animal Study	6	Not	Not Clinical but	Quantitative	
				Clinical	Positive Study	morphometry showed	
						decreased Collagen in	
						Bowel Wall	
	Carl (1998)68	Case Series-2	5	3ii	Likely to be	One patient completely	
		patients			Beneficial	resolved;the other	
]						stopped at 38 treatments	
						without improvement	
1	Gouello (1999)69	Case Series-36	5	3ii	Likely to be	2/3's of patients followed long	
		patients			Beneficial	term were improved or cured;	
						1/3 failed to improve	
	Bem (2000)70	Case Series-2	5	3ii	Likely to be	Both patients with anorectal	
		patients			Beneficial	ulcers resolved	
	Mayer (2001 )52	Case Series-1 O'	5	3ii	Likely to be	5 of 5 with rectal bleeding	
		patients			Beneficial	resolved; Statistically	
						significant decrease in late	
						morbidity score	
	Boyle (2002)71	Case Series-19	5	3ii	Likely to be	13 of 19 patients had major	
		patients			Beneficial	resolution of symptoms at	
						completion of hyperbarics	
1 J
An additional 8 case series reports are detailed in Table 3. Of the 114 cases reported in these 9 publications, 41 (36%) resolved and 68 (60%) improved after HBOztreatment.
The animal studies of Feldmeier57.6z demonstrate a decrease in fibrosis and an improvement in compliance in the small bowel of animals receiving HBOz before frank necrosis was evident. In these studies enough time was allowed to elapse for the vascular changes and fibrosis of late radiation injury to be established prior to autopsy. Characteristically, a latent period of several months to years is
observed to occur between the completion of radiation and clinical expression of radiation damage. 58
These case reports represent AHA level 5 evidence and the 2 controlled animal studies present AHA level 6 evidence. In the NCI models, the case reports are level 3ii evidence and the animal studies are not given a categorization.
Based on the consistency of the fmdings, an AHA lIb indication category is assigned (Fair to good evidence provides support). Applying the BM] scheme hyperbaric oxygen would be deemed to "Likely to be Beneficial" for this indication.
VII.Miscellaneous Abdominal Wall and Pelvic Injuries
Farmer and his colleagues16 in 1978 as part of a report, which included radiation injuries to man~
sites, reported a single case of vaginal necrosis that resolved with HBOz. Williams and associates 6
reported their results in treating 14 patients with vaginal radiation necrosis in 1992. Thirteen of 14
patients had resolution of their necrosis with hyperbaric treatment. One patient required 2 courses of HBOz. In 1996 Feldmeier and colleagues57 reported a series of 44 patients treated with various abdominal and pelvic injuries. The results in treating small and large bowel injuries have already been discussed above. Twenty-six of 31 patients who experienced injuries to the abdominal wall, groin, perineum, vagina or pelvic bones and who received at least 20 hyperbaric treatments had complete
18

UHM 2002, Vol. 29, No.1 - Literature Review for HBO and radiation injuries
resolution with treatment. This group included 6 patients with vaginal necrosis, all of who experienced complete resolution with treatment. The combined results reported in these 3 papers show complete resolution in 40 of 46 patients (87%). All but one of the 21 patients reported in these three papers with soft tissue vaginal necrosis were treated successfully. See Table 10.
Table 10.
Hyperbaric Oxygen as Treatment for Delayed Miscellaneous Radiation Injuries of the Abdomen and Pelvis
Author	I	Type of Report	
			
Farmer		Single Case Report	
(1978)16			
Williams	Case Series-15		
(1992)72	patients		
Feldmeier		Case Series-37	
(1996)63		patients	
NCI Grade
Clinical Evidence
Comments
5
3ii
Unknown Effectiveness Single case of vaginal
	necrosis resolved
5
3ii
Likely to be Beneficial 13/14 patients with vaginal necrosis resolved
5
3ii
Likely to be Beneficial
26/31 who received at least 20 HBO sessions resolved
including 10f 2 with pelvic osteoradionecrosis
All three publications in this section are AHA category 5 and NCI category 3ii. Based on the consistent positive outcome in treating pelvic injuries, an AHA category IIb is assessed to this indication. In the BM] system, HBOz is "Likely to be Beneficial" for miscellaneous pelvic and abdominal injuries. Additional support for treating these injuries is found in the response of pathologically similar injuries at other anatomical sites including bowel, bladder and soft tissue injuries of the head and neck.
VIII. Neurologic Injuries
Table 11 lists 14 publications wherein HBOz has been applied to radiation-induced neurologic injuries. 15, 73-85 These injuries include radiation myelitis of the spinal cord, radiation necrosis of the brain, optic nerve injury and brachial plexopathy.
Table 11.
Hart
"(1976)15
Case Series-5 myelitis patients and 1 with brain necrosis
5
3ii
Unknown Effectiveness (mixed result)
Sensory but no motor improvement for myelitis patients; brain patient
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UHM 2002, Vol. 29, No.1 - Literature Review for HBO and radiation injuries
						improved	
	Glassburn	Case Series-9	5	3ii	Likely to be Beneficial	6 of 9 improved	
	(1977) 73	patients					
		with					
		Myelitis					
.	Guy (1986f4	Case Series-4	5	3ii	Likely to be Beneficial	2 of 2 improved if started	
		patients				within 72 hrs;	
		optic nerve			(if initiated within	if beyond 72 hrs, neither	
'"					72 hrs)	responded	
	Roden	Case Series-13	5	3ii	Not likely to be	No patient had	
	(1990l5	patients			Beneficial	improvement in vision	
		optic					
		nerve					
		injury					
	Fontanesi	Single Case Report	5	3ii	Unknown	Visual acuity significantly	
	(1991)76				Effectiveness	improved	
		optic nerve			Single Positive Case	in spite of persistent tumor	
	Feldmeier	Animal Study of	6	Not Clinical	Not Clinical but	Onset of myelitis delayed	
	(1993)77	Myelitis			Positive Study	for 9 weeks in a	
						statistically significant	
						fashion for animals treated	
						prophylactica lIy	
	Borruat	Single Case Report	5	3ii	Unknown	Single patient with bilateral	
	(1993)78				Effectiveness	optic neuritis;	
						resolution in more recently	
						affected eye;	
						slight improvement in	
						earlier affected eye	
	Chuba	Case Series-10	5	3ii	Likely to be Beneficial	All ten initially improved; 4	
	(1997)79	patients				died from	
		brain				tumor; 5 of remaining 6 still	
		necrosis				improved	
	Leber	Case Series-2	5	3ii	Likely to be Beneficial	One lesion disappeared;	
	(1998)80	patients				the other was reduced in	
		brain necrosis				size	
	Calabro	Single Case report	5	3ii	Unknown	Progressive improvement	
	(2000)81				Effectiveness	following HBO	
		of radiation myelitis			Single Positive Case		
	Cirafis	Single Case Report	5	3ii	Unknown	No improvement with	
	i	of			Effectiveness	HBO, steroids	
	2000)8	rhombencephalopat			Single Negative		
		hy			Case		
						or anticoagulants	
	Pritchard	RCT: Brachial	1B	1ii	A Negative Study:	No improvement in	
	(2001)83	Plexopathy			No Benefit	brachial plexopathy	
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UHM 2002, Vol. 29, No.1 - Literature Review for HBO and radiation injuries
6 patients with lymphedema had significant reduction
Gesell
(2002)84
Case Series 29 Patients with Brain Necrosis
5
3ii
Likely to be Beneficial
Neurologic exam improved in 58%; steroid requirements decreased in 69%
Dear
(2002)85
Case Series 20 Patients with Brain Necrosis
5
3ii
Unknown Effectiveness
(Mixed Study)
Only 1 of 11 patients with Glioblastoma Multiforme improved; with other tumors 8/9 subjectively better and 3 of 5 tested objectively improved
Hart and Mainous15 in 1976 regorted 5 cases of myelitis treated with HEaz without significant
improvement. Glassburn and Brady 5 have reported 9 cases of myelitis in which patients received hyperbaric oxygen. Six of these 9 patients improved, including improvement in motor function. In 2000 Calabro and Jinkins81 reported a single case of myelitis in which the patient demonstrated progressive improvement including imaging documentation by MRI after treatment with HBaz. Feldmeier and colleagues77 reported a statistically significant delay in the onset of transverse myelitis in mice receiving HBaz in a prophylactic fashion. The clinical papers present AHA category 5 and NCI category 3ii evidence. The animal study provides AHA category 6 evidence.
There are no other known successful treatments for radiation-induced transverse myelitis and the consequences of myelitis are permanent paralysis and loss of sensation below the level of involvement. The experience reviewed above shows improvement in 7 of 15 patients. Based on the evidence available this indication would be considered "Indeterminate" by the AHA scheme and of "Unknown Effectiveness" in the BMJ model. In this desperate circumstance with a low likelihood of harms and no other effective treatment, HBaz based on humanitarian considerations appears
justifiable if initiated promptly.
Table 11 lists 6 publications in which HBaz has been applied to the treatment of brain necrosis. In the publication by Hart and Mainous15, a single case of brain necrosis is presented and this patient had improvement after treatment. In the paper by Chuba and associates 79, HBaz treatment led to temporary improvement initially in all 10 pediatric patients treated. Ultimately, four patients died as a result of their malignancy. At the time of their publication, five of the surviving 6 patients had maintained their improvement. Leber and colleagues8o reported the results in delivering HBaz to 2 patients suffering from radiation necrosis as a result of radiosurgery for arteriovenous malformations. Both patients had shrinkage of their lesions by imaging studies and one had complete resolution. In the paper of Cirafisi and Verderamae8z a single patient is presented who failed to respond to HBaz. The patient also failed to respond to steroids and anti-coagulants. Gesell and colleagues84 have reported the largest experience to date in applying hyperbaric oxygen to the treatment of radiationinduced brain necrosis at the 2002 Annual Meeting of the Undersea and Hyperbaric Medical Society. After hyperbaric oxygen treatment 17 of 29 patients had improved neurological examinations and in 20 of 29 patients, it was possible to decrease steroid requirements. At the same meeting Dear and
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UHM 2002,. Vol. 29, No.1 - Literature Review for HBO and radiation injuries
oJ>
associates85 presented their experience in treating 20 patients with radiation-induced brain necrosis. In 11 patients with Glioblastoma Multiforme, only one patient showed objective improvement. However, 7 of 11 patients were dead of tumor within a short time following HBOz and obviously had active tumor atthe time of treatment. It is very likely that the presence of tumor contributed to the neurologic deficits manifested by the patients. We have observed for some time that soft tissue necrosis lesions will not heal with HBOz therapy if tumor is present. In the other 9 patients with other tumors reported by Dear, eight were improved subjectively and 3 had objective improvement. All 6 of these publications represent AHA levelS and NCI level3ii evidence. Ifwe combine the results from these 6 publications, we fmd that 29 of 63 (46%) patients reported had some improvement after HBOz. No other treatments short of surgical resection of the necrotic focus have been effective. Based on the evidence available, this indication would be considered Category lIb (Acceptable and Useful based on fair to good evidence) by the AHA scheme and of "Likely to be Effective" in the BM] model.
Table 11 also includes four references reporting the results of HBOz in treatment of radiation induced optic neuritis. Again all four of these publications are case series including the single case report by Fontanesi.76 Only four of the 19 patients reported in these publications had visual improvement. Guy and Schatz74 report in their series that HBOz must be initiated promptly. In their series, two patients had complete restoration of their sight when they began HBOz treatment within 72 hours of loss of their sight. The other two patients who began HBOz at 2 weeks and 6 weeks after loss of vision had no improvement. In the paper by Borruat et al78, a single patient with bilateral radiationinduced optic neuritis had complete resolution in the more recently affected eye and improvement in the eye first affected. These results also suggest the importance of early intervention in order to obtain a positive outcome.
Based on these 4 publications, HBOz would be considered "Indeterminate" in the AHA scheme and "Unknown Effectiveness" in the BM] scheme. No other effective therapy exists for radiationinduced optic neuritis. In this desperate circumstance where permanent blindness is likely to occur, a trial of HBOz would appear to be justified based on humanitarian considerations. This therapy must be promptly initiated.
Finally, in regard to peripheral nerve injury treated by hyperbaric oxygen, Table 11 includes a randomized controlled trial conducted by Pritchard and colleagues 76. This study was designed to investigate the effect of HBOz in treatment of radiation-induced brachial plexopathy. This trial is
negative and fails to demonstrate a therapeutic advantage for HBOz. The median time from onset of
symptoms until enrollment into the trial was 11 years. As noted above in many neurological disorders, an effect of HBOz occurs only after prompt intervention. Importantly and interestingly, patients in the HBOz arm demonstrated statistically less post study deterioration in neurological function compared to the control group. Six patients in the HBOz arm also experienced a reduction in symptomatic lymphedema of the affected arm. Based on the presently available evidence, we would consider this indication for hyperbaric oxygen to be "Not Acceptable" in the AHA scheme and "Unlikely to be Beneficial" in the BM] scheme.
,\. ""
IX. Radiation Necrosis of the Extremities
	HBOz has also been reported as a useful therapy in radiation necrosis of the extremities. Table 12
lists two studies that discuss HBOz results in treating radiation injuries of the extremities.
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UHM 2002, Vol. 29, No.1 - Literature Review for HBO and radiation injuries
Table 12.
Hyperbaric Oxygen as Treatment for Radiation Injuries of the Extremities
Clinical Evidence
I Comments I
I Author I Type of Report [
AHA Grade I NCI Grade [
Farmer (1978)11
Single Case Report
5
3ii
Unknown Effectiveness Single Negative Case
1 of 1 failed to respond
Feldmeier (2000)86
Case Series-17 patients
5
3ii
Likely to be Beneficial
11 of 17 resolved; 11 of 13 if those lost to followup or with active cancer are excluded
In the report previously discussed by Farmer and his colleagues16 a single case of foot injury did not respond to HBOz (AHA level 5 evidence and NCI level 3ii evidence). In a series reported by Feldmeier and associates86, 17 patients with necrosis of the extremities treated with HBOz were reported (AHA level 5 and NCI level 3ii evidence). Sixteen of 17 patients had only soft tissue necrosis. Eleven of 17 had resolution with HBOz. If analysis is restricted to those patients in whom follow-up was available and in whom there was no evidence of recurrent cancer, eleven of 13 (85%) had resolution.
Although based on a small number of patients, this indication can be considered AHA level lIb and by the BM] system "Likely to be Beneficial". This determination is made in part based on successful intervention in soft tissue and bony radiation necrosis at other sites as reported above.
x. Hyperbaric Oxygen for Radiation Damage in Children
Published experience in applyil}f HBOz to radiation-induced injury in children is very limited.
The report of Chuba and colleagues7 of improvement in 10 pediatric patients with radiation-induced brain necrosis has already been discussed in the section on neurological nyuries. Ashamalla and colleagues87 reported their experience at the University of Pennsylvania in delivering HBOz to 10 children either as a prophylaxis against radiation injury or for treatment of established radiation necrosis. Six patients had pre-operative HBOz prior to dental extractions, root canals or coronoidectomies for mandibular ankylosis. All had successful outcomes without subsequent necrosis or surgical complications. Four other patients were treated for manifest radiation injury. One patient was treated for a 7ili cranial nerve neuropathy. Three others were treated for osteoradionecrosis (ORN) of various sites (mastoid bone, temporal bone and sacrum). HyPerbaric oxygen was given in conjunction with sequestromy for the ORN patients. The patients with ORN had complete resolution while the patient with the 7ili nerve injury did not have sustained improvement.
There are no compelling biochemical or physiologic reasons to think that the response of radiation injuries to HBOz in children is likely to be different to response in adults. Certainly children present special problems in conjunction with therapeutic radiation including complications not seen in adults such as growth retardation and decreased intellectual development as evidenced by a decrement
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UHM 2002, Vol. 29, No.1 - Literature Review for HBO and radiation injuries
in intelligence testing. No targeted research has been done in these special complications experienced in children; however, this would appear to be a fruitful area for future research.
Discussion:
1.
I
Few randomized controlled trials have been published to support efficacy of HBOz in treating delayed radiation injuries, yet the literature consistently provides lower levels of evidence supporting its application for this indication. Positive reports have been generated in multiple anatomic sites and in multiple tissue/organ types and from multiple investigators from a number of different countries
and continents. A characteristic of valid scientific methodology is consistency of reproducibility of outcome by other investigators in other venues. Tables 4 through 12 list 74 studies (some are included in more than 1 section). Of these 74 publications, all but 7 give positive indications of success with HBOz therapy. Four of the 7 negative reports are related to intervention with HBOz in neurological injuries where the pathophysiology is unique and where the promptness of intervention may be critical.
Experts are not in complete agreement as to the exact pathophysiology of delayed radiation injuries, but there is general agreement that endarteritis and resultant tissue hypoxia are consistent fmdings and contribute substantially to its etiology.88-9 3 Hyperbaric oxygen has been shown to enhance neovascularization at the microscopic level and to improve tissue oxygenation. Mechanisms by which HBOz offers therapeutic effect have been revealed by animal studies of Marx and associates
and by Feldmeier and collaborators. Marx et al9z have shown a dose de~endent increase in vascular
density in irradiated rabbits treated with HBOz. Feldmeier and co-workers Z,67 have shown evidence of decreased fibrosis in the pelvic and abdominal organs of mice receiving whole abdominal irradiation and then receiving post-irradiation HBOz compared to those receiving the same of radiation course
without HBOz. QQantitative morphometry identifying and contrasting the relative percentages of collagenous vs non-collagenous components in small and large bowel and kidney in these animals confmn the reduction of tissue fibrosis in animals receiving HBOz seven weeks after radiation exposure. 67,94,95
For this review, published materials were classified by anatomy or organ system. Perhaps from a pathological perspective, it would be more appropriate to divide tissues broadly into soft tissue and bony injuries. The response to and mechanisms of response to HBOz in soft tissue wounds resulting from radiation necrosis from the head and neck to the abdominal wall to the groin to the perineum to
the extremities is likely to be similar analogous to the response to antibiotics in cellulitis affecting soft tissues at many anatomic sites. Of course, the therapeutic agent must be deliverable in adequate dose to the site of pathology. Similarly, the response to HBOz in bone necrosis of the mandible is unlikely to be different from radiation necrosis of rib, pelvic bone or long bone of the extremities as long as an
appropriate arterial supply is available to allow oxygen transport to the site of radiation injury.
Damage to the nervous system, especially the central nervous system, certainly presents a special case and mechanisms whereby HBOz might be effective in the treatment of CNS injuries are not likely to be as simple as enhancing neovacularization. Though some have recently challenged the concept that ischemic injury of the CNS is irreparable, no one would deny that the repair of central nervous system tissues as the result of ischemia is very limited and that only very innovative research, e.g. stem cell transplantation, is likely to yield a substantial increment resolution of ischemic injury of the CNS.
The systematic literature review contained herein would certainly have benefited from a larger number of prospective randomized clinical trials and formal meta-analyses to substantiate
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UHM 2002. VoL 29. No.1 - Literature Review for HBO and radiation injuries
conclusions. In the preparing this review, the authors did not uncover large randomized controlled trials supporting other interventions for radiation injuries. A recent meeting convened at the National Cancer Institute designed to examine strategies for reducing radiation injuries presented the results of several pre-clinical studies but only identified a very few ongoing clinical trials. One clinical trial is ongoing which employs FGF7 (a fibroblast growth factor).96 One avenue of research, which appears
. promising based on pre-clinical study, is designed to block the renin-angiotensin system, but no clinical trials are yet underway. A number of trials are now published in the medical literature reporting some success in preventing radiation damage with Amifostine given during therapy as a radioprotector.97-101 Two papers have presented very early information from a pilot study and a small
retrospective review su~esting that pentoxifylline may have efficacy in the treatment of some
delayed radiation injuries. 2,103
The Baromedical Research Foundation is currently sponsoring the HORTIS trials, a series of
eight randomized blinded ~acebo-controlled trials investigating the effects of HB02 on a variety of
delayed radiation injuries. I Seven of the eight trials are designed to investigate the effects of HB02 on existing injuries in a variety of tissues. The final trial is designed to investigate the efficacy of HB02 as a prophylaxis against radiation injuries in a group of patients at high risk. When these studies are completed and analyzed, we should have type levidence elucidating the effects of HB02 for a
broad ran~ of radiation injuries. The HORTIS trial design makes use of the SOMA/LENT
system. lOS, This system for quantifying the severity of radiation injuries was the result of a cooperative project jointly developed by the RTOG, an NCI sponsored, cooperative research group, and the EORTC, the corresponding multi-national European radiation research cooperative group. These criteria for reporting the severity of radiation injuries should be applied to future reports of radiation toxicity or treatment of toxicity. In the SOMA/LENT system, for each organ the severity of injury is assigned a numerical grade. If a therapeutic modality is applied, its effects can be quantified by comparing pre-treatment and post-treatment scores. Until the results of these ongoing randomized trials are available, we must make do with limited evidence.
Other specialists dealing with other disease states also face the dilemma of producing evidencebased reviews in the absence of randomized prospective controlled trials. For instance, a recent publication by Bennett et al107 in the dermatology literature presents an evidence-based evaluation recommending the use of oral steroids in the treatment of infantile cutaneous hemangiomas based entirely on 10 case series and positive experience in a total of 184 patients.
In the BMj publication, Clinical Evidence7, therapies are reviewed even when no randomized controlled trials are available. For example in the review of treatment of cerebral metastases from metastatic breast cancer, the editors state, "We found no systematic review and no RCT's comparing one form of treatment with another.. .Non-randomized evidence suggests that symptoms from cerebral metastases can be successfully controlled with radiotherapy." The editors deem radiotherapy "Likely to be Beneficial" for breast cancer metastatic to the brain. This is standard treatment virtually anywhere in the world in spite of the absence of type 1 evidence.
Sackett and associateslOS define evidence-based medicine as the use of the best current evidence in making decisions about the care of individual patients. The best current evidence for HB02 in the treatment of radiation injury is presented in this paper in a systematic fashion. This evidence includes two randomized controlled trials, two prospective cohort controlled trials, numerous case series and several animal studies. The great majority of these papers are positive in their support of HB02 for delayed radiation injury. The associated harms are few and generally of minor consequence. The NCI model judges the strength of evidence with an eye to the severity of the problem and the consequences of effective treatment, especially when the treatment is life saving or enhances quality of life in a
25
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J		2.			
I					
		3.			
		4.			
		5.			
		6.			
			7.		
			8.		
			9.		
			10.		
			11.		
				12.	
				13.	
				14.	
				15.	
				16.	
				17.	
				18.	
				19.	
				20.	
				21.	
				22.	
	I				
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				24.	
	'4				
	I			25.	
				26.	
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UHM 2002. Vol. 29, No.1 - Literature Review for HBO and radiation injuries
highly significant fashion.6 It therefore seems appropriate to judge the success of HBOz for delayed radiation injmy as rather notable when the alternatives are death. radical surgery in already compromised patients or severe limitations in quality of life without successful treatment.
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30