Hyperbaric oxygen therapy for late radiation tissue injury in gynecologic malignancies

specifically for radiation damage to the anus and rectum; • the main indication for HBO2 therapy in gynecologic oncology is in the management of otherwise refractory chronic radiation injury; • HBO2 may provide symptomatic benefit in certain clinical settings (for example, cystitis, soft-tissue necrosis, and osteonecrosis); and • HBO2 may reduce the complications of gynecologic surgery in patients undergoing surgical removal of necrosis.

specifically for radiation damage to the anus and rectum; • the main indication for HBO 2 therapy in gynecologic oncology is in the management of otherwise refractory chronic radiation injury; • HBO 2 may provide symptomatic benefit in certain clinical settings (for example, cystitis, soft-tissue necrosis, and osteonecrosis); and • HBO 2 may reduce the complications of gynecologic surgery in patients undergoing surgical removal of necrosis.

BACKGROUND
In gynecologic cancers treated with a combination of external-beam radiation and brachytherapy, especially cervical, vaginal, and vulvar cancers, the apex of the vagina or perineum receives a high dose of radiation.The tolerance of the lateral apical vagina can be as high as 140 Gy, but the tolerance of the perineum is lower: up to 80 Gy can be tolerated if given over more than 6 weeks.The tolerance is less for the rest of the vagina and elsewhere in the pelvis, and high-dose radiation to those areas can result in complications.
Radiation-related complications that develop months or years after treatment with radiation are known as late radiation tissue injuries (lrtis) and are estimated to affect 5%-15% of all long-term survivors who have received radiation [1][2][3][4] .For patients with gynecologic malignancies, the estimated prevalence of lrti is 2%-4% among those who have undergone pelvic radiotherapy 5 .The absolute risk of radionecrosis increases with radiation doses greater than 60 Gy.The risk is disproportionately higher in patients who

Background
Late radiation tissue injury is a serious complication of radiotherapy for patients with gynecologic malignancies.Strategies for managing pain and other clinical features have limited efficacy; however, hyperbaric oxygen therapy (HBO 2 ) may be an effective option for some patients.

Methods
In a systematic review of the literature, the Ovid medline, embase, Cochrane Library, National Guidelines Clearinghouse, and Canadian Medical Association Infobase databases were searched to June 2009 for clinical practice guidelines, systematic reviews, randomized controlled trials, or other relevant evidence.Studies that did not evaluate soft tissue necrosis, cystitis, proctitis, bone necrosis, and other complications were excluded.

Results
Two randomized trials, eleven nonrandomized studies, and five supporting documents comprise the evidence base.In addition, information on the harms and safety of treatment with HBO 2 were reported in three additional sources.There is modest direct evidence and emerging indirect evidence that the use of HBO 2 is broadly effective for late radiation tissue injury of the pelvis in women treated for gynecologic malignancies.

Conclusions
Based on the evidence and expert consensus opinion, • HBO 2 is likely effective for late radiation tissue injury of the pelvis, with demonstrated efficacy undergo treatment with fraction sizes of 250 cGy or more daily.The mechanics of lrti are only partially understood.One major theory suggests that radiation causes progressive endarteritis of the small blood vessels, resulting in cellular hypoxia and damage to fibroblasts.This damage inhibits the ability of the irradiated tissue to repair itself, resulting in nonhealing ulcers.In patients inherently prone to radiation damage, it is probable that cells within organ stroma are unable to repair dna damage, resulting in a critically low volume of stem cells and lack of tissue healing.Within the pelvis, a radionecrotic wound can gradually progress to involve surrounding tissue, frequently resulting in vaginitis, proctitis, perineal ulcers, and vesicovaginal and rectovaginal fistulae.
Persisting symptoms often include pelvic pain, deep dyspareunia, frank hematuria, vaginal discharge, or frank ulceration and necrosis.Ulceration and necrosis can be particularly disabling, being characterized by pain and a malodorous serosanguineous discharge.Affected patients often become socially isolated and are at risk for depression, nutritional deficiency, or repeated hospitalizations 5 .
Medical treatment typically involves topical wound care and surgical repair, but unfortunately, treatment failure is common.Surgical repair of fistulae related to radiation necrosis is not only technically difficult, but has met with only limited success because of a compromised blood supply in the skin and myocutaneous flaps used 5 .
Hyperbaric oxygen therapy (HBO 2 ) has been used as a treatment modality to promote repair of radiationinduced vascular changes.Transcutaneous oxygen measurements 4 years after HBO 2 have revealed nearnormal levels, implying that HBO 2 -induced angiogenesis is essentially permanent.Thus, HBO 2 is the first available treatment for delayed radiation injuries that potentially modifies the underlying mechanism of tissue damage and that is associated with healing of otherwise treatment-refractory ulcerated tissue 6 .Preoperative HBO 2 can contribute to a higher rate of surgical success.
The mechanism by which HBO 2 is thought to treat radiation tissue injury is the induction of neovascularization that reverses tissue hypoxia.The stimulus for angiogenesis appears to be mediated through macrophages responding to the oxygen gradient between the damaged hypoxic cells and the surrounding normal tissue 7 .Other biochemical pathways involved include mobilization of stem cells from bone marrow 8 and vasculogenesis 9 , resulting in elevated levels of vascular endothelial growth factor 10 .The subacute and chronic phases of radiation wounds are particularly suited to this form of therapy.The HBO 2 acts to stimulate collagen formation at the wound edges through elevation of local tissue oxygen tension.The growth of new microvasculature, which is dependent on a collagen matrix, is greatly enhanced in this setting and allows for re-epithelization to occur.The HBO 2 also stimulates fibroblast proliferation.A range of studies has characterized mechanism of action, treatment approaches, economic evaluation, and other aspects of HBO 2 5,11-15 .

OBJECTIVES
This evidence-based clinical practice guideline aims to provide recommendations for the use of HBO 2 therapy in lrti with respect to soft-tissue necrosis, cystitis, proctitis, bone necrosis, and other complications in women treated with radiation for gynecologic cancers.Although the importance of preventing lrti is recognized, this guideline does not address prevention, but rather treatment of lrti.

Question
Is HBO 2 effective in treating lrti with respect to softtissue necrosis, cystitis, proctitis, bone necrosis, and other complications in women who have undergone radiation therapy for gynecologic malignancies?

Target Population
This clinical practice guideline applies to women treated with radiation for gynecologic cancers who have developed lrti (soft-tissue necrosis, cystitis, proctitis, bone necrosis, and other complications) and for whom the use of HBO 2 therapy is being considered.

Target Users
This clinical practice guideline is intended to inform health practitioners on the use of HBO 2 among women with lrti consequent to radiation for gynecologic malignancies.It is also intended for use by health authorities and key administrative and policy decisionmakers to inform policy decisions concerning the use of HBO 2 and by cancer survivors with gynecologic malignancies to assist in making informed decisions on treatment options for lrti.

Guideline Development
The review process for this guideline was developed based on • the U.K. National Institute for Health and Clinical Excellence overview of clinical guideline development for stakeholders, the public, and the National Health Service 16 ; • Cummings and Rivara's methodology for reviewing manuscripts 17 ; and • the agree collaboration 18 .

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With that methodologic foundation, the guideline recommendations were drafted by 2 radiation oncologists from the Tom Baker Cancer Centre, with support from the Guideline Utilization Resource Unit and the Alberta Gynecologic Oncology Provincial Tumour Team.Members of the Alberta Gynecologic Oncology Provincial Tumour Team include gynecologic oncologists, medical oncologists, radiation oncologists, nurses, pathologists, and pharmacists.The evidence base for the present guideline was informed by a systematic review of the literature, which was current to June 2009.
Before completion, the guideline was distributed to an external review panel consisting of 4 reviewers (a gynecologic oncologist, 2 radiation oncologists, and a clinical expert in hyperbaric medicine) for feedback concerning the collection and interpretation of the evidence and the development and content of the recommendations.Feedback from reviewers was summarized, reviewed, and addressed by the guideline developers in a teleconference.Finally, in an internal review of the guideline, members of the Alberta Gynecologic Oncology Provincial Tumour Team were invited to submit feedback on the draft guideline.After the feedback was incorporated, the guideline was circulated back to the group for consensus approval.Final consensus was reached through an informal voting process.The literature will be periodically reviewed, and the guideline will be updated as new or compelling evidence is identified.

Literature Search Strategy
The Ovid medline (1965 through June 25, 2009), embase (1980 through June 25, 2009), Cochrane Library (2000 to June 25, 2009), National Guidelines Clearinghouse, and Canadian Medical Association InfoBase databases were searched to June 2009 for clinical practice guidelines, systematic reviews, randomized controlled trials, or other relevant evidence deemed eligible to inform the topic.Reference lists of related papers and recent review articles were also scanned for additional citations.
Literature search terms included "hyperbaric oxygen therapy" or "hyperbaric oxygenation"; "pelvic" or "pelvis" or "gynecol*" or "gynecology"; and "radiation injury" or "proctitis" or "cystitis" or "lesions."The search was limited to articles in the English language.The search identified 45 citations; of those, 13 were selected for full-text review.

3.3.1
Inclusion Criteria Articles were selected for inclusion in the review of the evidence if they reported on patients with pelvic malignancies that were experiencing lrti after receiving radiotherapy for treatment of their disease, and they investigated the use of HBO 2 in that treatment population.Preference was given to clinical practice guidelines, systematic reviews, or randomized controlled trials; however, given the anticipated paucity of data, nonrandomized studies addressing the topic and indirect evidence involving other oncology patient populations treated with HBO 2 were also deemed eligible if insufficient primary evidence were to be available.

3.3.2
Exclusion Criteria Articles were excluded from the review of the evidence if they were qualitative or descriptive studies, opinion papers, letters, or editorials.Because of a lack of translation services, articles in languages other than English were excluded from the review of the evidence.

Synthesizing the Evidence
Because of differences in outcomes studied and a limited sample size, it was not appropriate to conduct a meta-analysis of the data.
There is evidence that HBO 2 has efficacy in lrti of the pelvis, rectum, bladder, soft tissue, and bone.Among women experiencing lrti from treatment for gynecologic malignancies, the response rate to HBO 2 is of the order of 70%.Studies have found positive effects and a range of specific response rates for various clinical features of lrti (including cystitis, proctitis, and other gastrointestinal complications) and pain [23][24][25][26][27] .There is some evidence to suggest that outcomes are better when HBO 2 is initiated by 6 months from the start of symptoms rather than being delayed beyond that point 26 .
Randomized controlled trials have demonstrated that HBO 2 significantly improves pelvic radiation symptoms.Sidik et al. 19 showed that, compared with control patients, women undergoing HBO 2 [100% oxygen at 2.0-3.0 atmospheres absolute (ata) for at least 18 sessions] experienced significantly ( p = 0.008) fewer side effects from pelvic radiation (median dose not reported) and significantly better quality of life ( p < 0.001 after Current OnCOlOgy-VOlume 18, number 5 Copyright © 2011 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).Evidence from earlier nonrandomized studies suggests that HBO 2 is particularly effective in the treatment of radiation-induced hemorrhagic cystitis, especially in patients who have failed to improve with the use of other treatment modalities 28 .Fletcher et al. 29 demonstrated complete resolution of hemorrhagic cystitis in 64% of patients treated with HBO 2 once daily for a mean of 14 sessions or until resolution.A response rate of 86% has also been reported 30 .Furthermore, the benefit of HBO 2 appears to be long-lasting (for example, after more than 5 years) in some patients 31 .
Moderate success for HBO 2 as a treatment for soft-tissue necrosis has also been reported.Williams et al. 21prospectively examined the therapeutic effects of HBO 2 on radiation-induced soft-tissue necrosis in 14 patients who had previously received treatment for a gynecologic malignancy.Fourteen patients whose necrotic wounds failed to heal after 3 months of conservative therapy underwent 15 courses of HBO 2 .All patients with vaginal radiation necrosis or rectovaginal fistula experienced complete resolution of necrosis with HBO 2 ; only 1 treatment failure occurred.Other studies have found similarly positive effects and response rates for a range of clinical features of lrti, including proctitis, cystitis, proctitis and other gastrointestinal complications, and pain [22][23][24][25][26][27] .
A systematic review conducted by Bennett et al. 12 concluded that, for patients with lrti affecting tissues of the head, neck, anus, and rectum, HBO 2 is associated with improved outcomes.Application of HBO 2 also appeared to reduce the risk of osteoradionecrosis after tooth extraction in an irradiated field.An earlier systematic review of 74 publications reporting on the use of HBO 2 in the treatment or prophylaxis of delayed radiation injury found that all but seven publications reported a positive result for HBO 2 .The authors concluded that HBO 2 should be recommended for delayed radiation injuries in soft tissue and bone at most sites 39 .
However, the evidence remains preliminary overall.A 2005 report from Cancer Care Ontario's Program in Evidence-Based Care concluded that the evidence from clinical studies is currently insufficient to warrant further investment in HBO 2 for new indications in the treatment or prevention of radiation-induced injuries.The report also indicated that the state of the evidence does not justify withdrawing this intervention where it is currently used as standard practice.The report declared that bettercontrolled studies are needed to confirm the clinical utility of HBO 2 33 .By contrast, the BC Cancer Agency 34 lists referral for HBO 2 therapy as an option for selected patients with lrti, and the Scottish Intercollegiate Guidelines Network 35 , writing on the diagnosis and management of head-and-neck cancer, recommended that HBO 2 facilities should be available to selected patients with head-and-neck cancer.Likewise, at the European Concensus Conference on Hyperbaric Medicine, the European Society for Therapeutic Radiology and Oncology and the European Committee for Hyperbaric Medicine listed myelitis and plexopathy, proctitis and enteritis, cystitis, radionecrosis of the larynx, and osteoradionecrosis as indications for the use of HBO 2 40 .There are risks and benefits associated with HBO 2 .It is advisable to have all potential candidates evaluated by an experienced hyperbaric physician to determine "fitness to dive" (that is, to assess treatment-associated risks) 36 .Of particular concern are patients who present with middle or inner ear disorders, congenital heart disease, claustrophobia, chronic obstructive pulmonary disease, high fever, cataracts, pregnancy, or use of a pacemaker or an epidural pain pump, among others 36,37 .Absolute contraindications to the use of HBO 2 include untreated pneumothorax or untreated cancer (that is, concurrent use of bleomycin, cisplatin, disulfiram, doxorubicin, or mafenide acetate) 37 .However, the use of HBO 2 therapy is considered safe when the chamber is properly installed according to municipal and provincial regulations and when operators and attendants are properly trained.Operators should be able to manage any serious complications that could be encountered by patients and should be supervised by a physician trained in hyperbaric medicine 38 .
Can HBO 2 increase the risk of cancer recurrence?A retrospective analysis of 22 patients with recurrent head-and-neck cancer concluded that HBO 2 increases the risk of cancer re-recurrence: 5-year disease-free survival rates were lower in patients receiving HBO 2 (32.7% vs. 70.0%,p = 0.048) 41 .However, as Hermann and Carl and Feldmeier et al. noted, the high risk of stratification bias and small sample size are problematic, and larger controlled trials have shown no effect or an inhibitory effect of HBO 2 on recurrence 42,43 .Nevertheless, patients should be clinically cancer-free at the onset of tissue ulceration, and recurrent cancer should be ruled out before HBO 2 is initiated.

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DISCUSSION
There is little strong evidence to definitively recommend HBO 2 for women with lrti secondary to radiation for gynecologic malignancies; the area has not been well studied.But despite the limited evidence, several studies showed positive therapeutic effects with HBO 2 for lrti of the pelvis, and several other studies suggest that HBO 2 may be beneficial for improving quality of life in patients with radiation toxicity after treatment for pelvic malignancy.Overall, the body of evidence, although modest, favors HBO 2 as a therapeutic option.
However, the mechanism of action of lrti and the evidence supporting clinical benefit with HBO 2 are thought to be similar after radiation treatment administered for gynecologic malignancies and radiation treatment administered for other indications and to other parts of the body.A cogent argument can be made that positive outcomes in studies of HBO 2 treatment for lrti together contribute to a broader field of evidence.This field of evidence suggests that HBO 2 for lrti related to chronic vascular injury can be anticipated to be of benefit in many clinical scenarios.
If HBO 2 is being considered as a therapeutic option, the clinical condition to be treated (that is, pain from cystitis, proctitis, bone necrosis, soft-tissue necrosis, and so on) should be quantified, and clinical endpoints should be determined, case by case before the HBO 2 is initiated.Currently, no strong evidence or agreement has emerged to indicate the most appropriate dosing regimen; however, treatment typically consists of once-daily treatments at 2.0-2.5 ata, usually for 90 minutes (range: 60-120 minutes), 5 days weekly, for up to 40 treatments, depending on the patient's condition 12 .In general, after 20-25 treatments with HBO 2 , a clinical evaluation should reassess the patient's condition and determine whether significant improvements were achieved.In the absence of significant improvements, the case should be re-evaluated to determine whether HBO 2 is an appropriate treatment option.
Some organizational barriers may be associated with the use of HBO 2 , including access to equipment and funding, whether for direct costs (per course of treatment) or indirect costs (such as accommodations for patients, staffing requirements, time requirements, treatment for side effects, and referring physician knowledge) 44 .
To conclude, modest direct and emerging indirect evidence supports HBO 2 as being broadly effective for lrti of the pelvis in women treated with radiation for gynecologic malignancies.Treatment with HBO 2 should be considered for women for whom conservative care has failed.Emerging interest in validated tools will support collaborative approaches to document outcomes across jurisdictions.Acumen in HBO 2 will benefit from more rigorous reporting of outcomes from its use in lrti populations.

RECOMMENDATIONS
The recommendations that follow are based on • a modest quality of evidence that supports the use of HBO 2 for lrti, • review by external content experts, and • the expert consensus opinion of the Alberta Gynecologic Oncology Provincial Tumour Team.
The recommendations apply to women presenting with lrti, including soft-tissue necrosis, cystitis, proctitis, bone necrosis, and other complications subsequent to radiation therapy for gynecologic malignancies.
• HBO 2 is effective for lrti, particularly that of head, neck, anus, and rectum.That is, there is an emerging field of evidence, with contributions from specific and diverse areas of clinical study, of positive outcomes in patients with lrti involving head, neck, anus, or rectum.• Among women with lrti secondary to radiation for gynecologic malignancies, the main indication for the use of HBO 2 therapy is the management of treatment-refractory chronic radiation injury.• There is evidence for symptomatic benefit with the use of HBO 2 therapy in certain clinical settings (cystitis, soft-tissue necrosis, or osteonecrosis) after radiotherapy for cervical cancer.The small number of case series and the low patient numbers limit the construction of more specific recommendations; however, HBO 2 should be considered for women in whom conservative care fails.In patients being considered for surgical removal of necrosis, limited but consistent evidence supports the use of HBO 2 to reduce the complications of gynecologic oncology surgery, purported to occur through the stimulation of small-vessel angiogenesis.

ACKNOWLEDGMENTS
The authors acknowledge the contributions of Drs.Prafull Ghatage, Alexandra Schepansky, Harold Lau, and Simon Pavamani to the development of this clinical practice guideline.

CONFLICT OF INTEREST DISCLOSURES
There authors have no conflicts of interest to declare.

table i
Efficacy of hyperbaric oxygen therapy for the treatment of late radiation tissue injury to the pelvis Reference a Significant (p ≤ 0.001) compared with control group.bAuthorsreported that most patients received at least 18 sessions.cSignificant(p ≤ 0.01) compared with control group.Current OnCOlOgy-VOlume 18, number 5Copyright © 2011 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).