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Current management of radiation cystitis: A review and practical guide to clinical management

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  • Bart's Health NHS Trust

Abstract

Haemorrhage is a frequent complication of radiation cystitis leading to emergency presentations in patients with prior pelvic radiation therapy. Standard initial patient management strategies involve resuscitation, bladder washout with clot evacuation and continuous bladder irrigation. Beyond this, definitive surgical treatment is associated with significant morbidity and mortality. Alternative less invasive management options for non‐emergent haemorrhagic cystitis include systemic medical therapies, hyperbaric oxygen, intra‐vesical therapies and laser ablation. However, evidence to support and compare treatment for haemorrhagic radiation cystitis is limited. Herein, a literature search pertaining to the current management of haemorrhagic cystitis was conducted. With evaluation of existing literature, this narrative review also provides a stepwise clinical algorithm to aid the urologist in treating patients presenting with complications associated with radiation cystitis. This article is protected by copyright. All rights reserved.
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doi: 10.1111/bju.14516
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MR. NIALL F DAVIS (Orcid ID : 0000-0002-5298-1475)
DR. DECLAN MURPHY (Orcid ID : 0000-0002-7500-5899)
DR. NATHAN LAWRENTSCHUK (Orcid ID : 0000-0001-8553-5618)
Article type : Review
Current management of radiation cystitis: A review and practical guide to
clinical management
Claire Pascoe1,2, Catriona Duncan2,3, Benjamin W Lamb4, Niall F Davis2, Thomas H Lynch5, Declan G
Murphy1, Nathan Lawrentschuk1,2
1. Department of Cancer Surgery, Peter MaCallum Cancer Centre, Melbourne, Australia
2. Department of Urology, Austin Health Heidelberg, Australia
3. North Eastern Urology, Heidelberg, Australia
4. Department of Urology, Cambridge University Hospitals NHS Foundation Trust, Cambridge,
United Kingdom.
5. Department of Urology, St James Hospital, Dublin 8, Ireland.
Corresponding Author
A/Prof Nathan Lawrentschuk
E: lawrentschuk@gmail.com
M: +61 488 088 240
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Keywords: radiation, radiotherapy, cystitis, management, haemorrhage, bleeding, bladder
Abbreviation
Term
ATMs
atmospheres
BPH
Benign prostatic hypertrophy
CBI
Continuous bladder irrigation
CR
Complete response
GAG
glycosaminoglycan
HBO(T)
Hyperbaric oxygen (therapy)
IMRT
Image modulated radiation therapy
NKTCs
Natural killer cells
NR
Not recorded
PR
Partial response
QoL
Quality of Life
SPP
Sodium pentosan polysulphate
TCDO
tetrachlorodecaoxygen
TF
Treatment failure
YAG
Yttrium-aluminium-garnet
Abstract
Haemorrhage is a frequent complication of radiation cystitis leading to emergency presentations in
patients with prior pelvic radiation therapy. Standard initial patient management strategies involve
resuscitation, bladder washout with clot evacuation and continuous bladder irrigation. Beyond this,
definitive surgical treatment is associated with significant morbidity and mortality. Alternative less
invasive management options for non-emergent haemorrhagic cystitis include systemic medical
therapies, hyperbaric oxygen, intra-vesical therapies and laser ablation. However, evidence to
support and compare treatment for haemorrhagic radiation cystitis is limited. Herein, a literature
Accepted Article
This article is protected by copyright. All rights reserved.
search pertaining to the current management of haemorrhagic cystitis was conducted. With
evaluation of existing literature, this narrative review also provides a stepwise clinical algorithm to
aid the urologist in treating patients presenting with complications associated with radiation cystitis.
1.0 Introduction
Chronic haemorrhagic cystitis occurs up to 5% of patients following pelvic radiotherapy [1]. Although
the advent of intensity modulated radiation therapy (IMRT) may decrease radiation induced bladder
toxicity; robust data on long-term outcomes are limited [2]. The response of the urinary bladder to
radiation treatment can be classified into acute or subacute reactions that typically occur within 3-6
months of radiation treatment and late reactions that occur after six months. Delayed radiation
induced endothelial cell damage and perivascular fibrosis result in ischaemia and obliterative end
arteritis leading to a range of symptoms including urinary frequency, urgency, pelvic pain and
haematuria[3].
Complications associated with radiotherapy account for up to 7% of emergency urology admissions
[4]. Initial management of radiation cystitis with haemorrhage frequently involves a sequential
algorithm consisting of initial resuscitation and reversal of anticoagulation as clinically appropriate,
copious bladder washouts with clot evacuation, followed by continuous bladder irrigation (CBI) and
blood transfusions as required. Characteristic cystoscopy findings are telangiectasia with friable
erythematous mucosa [5]   
of life (QoL) with persistent bleeding resulting in life threatening hypovolaemic shock [6]. The
management of complex patients on anticoagulation requires balanced clinical decisions regarding
the risks and benefits of blood transfusions and cessation of anticoagulation by the treating
physician, however often short periods without anticoagulation may be required to interrupt the
pathological cycle. Urinary diversion and cystectomy for end-stage haemorrhagic cystitis is
associated with a 44% mortality rate [7, 8]. Alternative less invasive management options for non-
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emergent haemorrhagic cystitis include systemic medical therapies, hyperbaric oxygen, intravesical
therapies and laser ablation. These treatment strategies have several limitations including difficulty
obtaining and administering some of the more historical treatments, such as formalin and alum, in
the contemporary clinical setting. There is also a dearth of level one evidence for the efficacy of such
treatments. A further limitation is the absence of a pre-determined management algorithm
regarding best clinical practice for patients presenting with symptomatic radiation induced
haemorrhagic cystitis. In this narrative review, we summarise available therapies for treating chronic
radiation induced hemorrhagic cystitis and propose a practical management algorithm.
2.0 Methods
A literature search was undertaken using Medline, Embase, Pub Med and Google Scholar. The
following terms were entered into the search algorithm to identify peer-reviewed articles that
investigated management strategies for radiation induced hemorrhagic cystitis:  
, , haemorrhage or hemorrhage A further search of commonly used
          
     Results were limited to publications in the English language,
involving adult human patients and published after 1990. Reference lists were checked to identify
relevant studies not captured in the initial search. Reviews and case reports were excluded and,
where possible, studies including patients who had received either radiation or cyclophosphamide,
as a precursor, were filtered to assess intervention effect on those who received radiation therapy
only. Abstracts and complete manuscripts were reviewed individually by two authors and
discrepancies reviewed by a third party.
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            
radiation therapy and pelvic radiation for any cause. For comparative purposes, outcomes were
classified as either complete response (CR) corresponding to resolution of haematuria, partial
response (PR) corresponding to improvement but not resolution of haematuria or treatment failure
(TF) corresponding to requirement of alternative intervention for persistent severe haematuria.

a trial.
224 manuscripts were identified through database search and a further five were included after
identification through other sources. After removal of duplicates and further screening by title and
abstract to ensure adherence with inclusion and exclusion criteria 51 articles were further assessed
for eligibility. Due to the heterogeneity of the clinical causes for haemorrhagic cystitis, articles were
excluded due to absence of previous pelvic radiation as a underlying cause of the haemorrhagic
cystitis. A total of 28 studies were included for qualitative synthesis. Within these studies, patient
groups were small and not divided by underlying malignancy and as such all eligible studies including
patients with haemorrhagic radiation cystitis were reviewed.
3.0 Treatment options
A variety of treatment options are described for radiation induced hemorrhagic cystitis. These
management strategies can be subclassified into systemic medical therapies, hyperbaric oxygen,
intravesical, ablative, interventional radiological and definitive surgical techniques. Their advantages,
disadvantages and most recent comparative data on clinical efficacy are discussed in detail below.
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3.1 Systemic therapies
Medical systemic therapies for haemorrhagic cystitis are appealing as they are non-invasive
and circumvent inpatient hospital admission (Table 1). WF10 is an intravenous formulation,
manufactured from the drug substance OXO K993, also referred to as
Tetrachlorodecaoxygen (TCDO). Its proposed mechanism of action for treating haemorrhagic
radiation cystitis relies on the model of a post irradiated bladder being in a state of chronic
inflammation. WF10 induces natural immunity and stimulates cellular defence mechanisms
through its actions on natural killer cells (NKTCs), cytotoxic T-lymphocytes, and modification
of the monocyte-macrophage system. It reduces inflammation promptly so that a host-
derived healing can commence [9]. In one randomised controlled trial, Veerasan et al.
demonstrated that patients treated with WF10 (n=37) had a significantly decreased rate of
recurrent haematuria recurrence after 12 months (47% vs 77%, p=0.01) [9]. A potential
limitation to this study is that the treatment failure group in both arms may be over-
           
response rate with WF10 in detail.
Sodium pentosan polysulphate (SPP) is a synthetic sulphated polysaccharide that is used to
decrease urothelial permeability by replacing defective GAGs. Sandhu et al. assessed SPP,
oral administration of 100mg three times daily, for managing radiation induced
haemorrhagic cystitis in 60 patients. In total, 51 patients were available for follow-up and
the dose was gradually reduced to a maintenance dose of 100 mg in 21 patients due to PR.
In 10 patients SPP was stopped due to CR. A limitation with medical therapies, as noted by
[10]. The onset of action was 1-8 weeks. In this timeframe, 15
patients required inpatient admission for bladder irrigation; of which 5 required irrigation
under general anaesthetic and 14 required blood transfusions [10].
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Tranexamic acid has been used to treat urological haemorrhagic emergencies however
evidence of efficacy in the haemorrhagic radiation cystitis patient is lacking. It can be
administered in the initial resuscitation and conservative management phases of active
haemorrhage in patients with prior radiotherapy. As tranexamic acid acts by inhibiting
fibrinolysis, attention must be directed at preventing formation of large thrombi with
resultant clot urinary retention. Tranexamic acid has been associated with increased risk of
thromboembolic events however the evidence not clear. It may be considered in
problematic acute surgical bleeding such as in haemorrhagic radiation cystitis however
complications of clot retention limit its use. [11]
3.2 Hyperbaric oxygenation
The underlying pathophysiology of radiation cystitis involves a progressive end arteritis that
leads to poor tissue oxygenation and eventual tissue ischemia. Necrosis and tissue sloughing
ensues with fibroblast deposition on ischaemic tissue layers. Compensatory
neovascularisation and telangiectasia leads a friable vascular network with resultant
haematuria. Hyperbaric oxygen (HBO) therapy increases oxygen delivery to tissues by
increasing the amount of dissolved oxygen in the plasma to induce and restore normal
reparation of granulocytes and fibroblasts. Administration of HBO has been shown to induce
neo-[12-14]. Studies reporting on
outcomes of HBO are mainly retrospective in patients who have failed conservative
management for radiation-induced haemorrhagic cystitis. Their main findings are
summarised in table 2 with complete resolution of haematuria occurring in 34-87.5% of
patients. Commencement of HBO within 6 months of haematuria increases the potential of
complete resolution to 96% [15]. With HBO, patients spend 90 minutes 5-7 days per week in
a hyperbaric chamber inspiring 100% oxygen between 2-2.4 atmospheres (ATMs). A total of
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40 HBO treatments extending over an 8-week period are typically administered [16]. The
follow up of patients following HBO varied between 12-120 months, with the majority of
patients being followed up for a mean of 24 months of less, as outlined in table 2. As such,
the evidence for long-term efficacy of HBO in the treatment of haemorrhagic radiation
cystitis is lacking.
3.3 Intravesical therapies
Contemporary evidence and outcomes for intravesical therapies are summarised in Table 3.
Response rates with these agents typically range from 60-90%. Historical evidence-based
intravesical therapies for the treatment of haemorrhagic radiation cystitis are instillations of
formalin and alum [17]. Formalin functions by precipitating cellular proteins within the
epithelial layer causing occlusion fixation of the telangiectatic and friable microvasculature.
There is limited contemporary evidence on the use of formalin and devastating
complications, such as patient mortality, have been described with concentrations of 2-4%.
Notably, lower concentrations demonstrate equivalent clinical efficacy with a lower
complication rate [18, 19]. A contemporary study of 8 patients with haemorrhagic radiation
cystitis, treated with formalin instillation, 7 of whom had failed other therapies, describes a
response in 6, patients. However, 5 of the 8 patients required blood transfusions within 30
days of instillation, one patient developed acute kidney injury and respiratory failure
requiring intensive care management. Urinary diversion was required in 2 patients that did
not respond and in 1 patient that developed recurrent symptoms [20]. Therefore, formalin is
only recommended in cases of intractable haemorrhagic cystitis that may require urinary
diversion [21]. Aluminium salts (usually potassium or ammonium aluminium sulphate) act by
precipitating proteins on the surface of cells. Intravesical instillation of alum is not as
effective as formalin but is associated with an improved side-effect profile and may
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represent an early treatment option if initial more conservative measures are unsuccessful.
[17]
More recently, novel intravesical therapies have aimed to replenish the glycosaminoglycan
(GAG) protective layer to reduce exposure of underlying epithelial cells to host urine.
Hyaluronic acid is a major mucopolysaccharide than can be instilled into the urinary bladder.
It has immunomodulatory properties that enhance connective tissue healing [22]. Epsilon
aminocaproic acid inhibits fibrinolysis to counteract urokinase on exposed telangiectatic
vessels in the post-radiation bladder and can be instilled into the bladder. Singh et al.
described intravesical instillation in 37 patients with intractable haemorrhage associated
with radiation or chemotherapy induced cystitis and reported a partial or complete response
rate in 34 patients (92%) [23]. Other intravesical therapies have been described in smaller
  er nitrate (0.01-0.4%) was ineffective for managing haemorrhage in 9
patients with radiation cystitis [24]. Several other agents, including prostaglandins,
botulinum toxin, polydeoxyribonucleotides and early placental extract, have also been
reported with limited response rates [22].
3.4 Ablative therapies
Ablation and coagulation of ruptured submucosal vasculature with laser (yttrium-
aluminium-garnet [YAG] and Greenlight©) therapy or argon beam therapies is advantageous
as both modalities can immediately control haemorrhage and are associated with complete
response in 75-97.5% of cases (Table 4). Disadvantages with these modalities are
requirement of general or spinal anaesthesia. Greenlight© laser can ablate blood vessels
with selective absorption of green light by intravascular oxy-haemoglobin thereby sparing
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the surrounding tissue [25]. Conversely, the YAG laser is non-selective and has an increased
risk of bladder or bowel perforation in conjunction with irritative post procedural urological
symptoms due to sloughing of necrotic tissue [26]. Argon beam coagulation does not use
laser technology. Instead, the bladder is filled with argon gas and an argon probe is directed
approximately 3mm from the vessel and a monopolar current is aimed towards it. Uniquely,
argon ablative therapy has a safety mechanism for preventing perforation as the current
follows the path of least resistance and moves onto adjacent tissue after coagulation has
been achieved. Also, the depth of ablation can be altered by adjusting power and gas flow
settings [5].
3.5 Interventional radiological
There is limited evidence on arterial embolisation for managing haemorrhagic radiation
cystitis. Small case series describe clinical scenarios of haemorrhagic radiation cystitis
combined with additional causes of intractable haematuria originating from the urinary
bladder or prostate gland. In these series, resolution of haematuria varies from 90-100% and
is dependent on the underlying patient group requiring embolisation [27, 28]. Long-term
resolution of haematuria ranges from 70-81% after a median follow-up of 16-18 months.
Loffroy et al [29] found that embolisation can be selected to treat any cause of intractable
haematuria (including radiation cystitis) as complete resolution occurs in 92.6-100% of
patients. Notably, depending on the selectivity of embolization, ischaemic complications
occur in 10-62.5% and may include skin or bladder necrosis, gluteal paresis, Brown-Sequard
syndrome, and perineal or buttock pain.
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3.6 Definitive surgical treatment
Urinary diversion with or without cystectomy can be performed if all other less invasive
treatment modalities have failed. One series on 21 patients undergoing cystectomy and
urinary diversion for intractable haemorrhagic cystitis demonstrated that 42% of patients
developed a complication that was either Clavien-Dindo Grade III or Grade IV during the
perioperative period. Furthermore, the 90 day mortality was 16% and overall survival at one
year was 84% [8].
4.0 Management algorithm
There are no widely adopted definitive treatment algorithms for managing patients with radiation-
induced haematuria. Therefore, definitive and effective treatment of this patient population is often
challenging for the urologist. To optimise clinical outcomes in this difficult patient cohort; we
propose the following stepwise, evidence-based approach to treatment of the acutely haemorrhagic
patient (Fig. 1). A clinical guide to each step in the algorithm can be found in Table 5.
4.1 Haemorrhagic radiation cystitis with active bleeding
Acute active bleeding in the setting of previous pelvic radiotherapy can result in
hypovolaemic shock. Therefore, we advocate inpatient admission for patients with acute
haemorrhagic radiation cystitis. Initial management involves stabilisation with fluid
resuscitation, insertion of a large 24-26Fr 3-way indwelling catheter (IDC), manual washout
with extensive clot evacuation and commencement of continuous bladder irrigation (CBI).
Tranexamic acid, administered orally, intravenously or intravesically, may be considered in
the initial conservative management of urological haemorrhage.[30]
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A thorough patient history and physical examination should be performed to exclude other
causes of haematuria such as urinary tract infection, anti-thrombotic agents, pre-existing
urological malignancy, benign prostatic hyperplasia (BPH), urinary stone disease and known
underlying coagulopathies. Laboratory investigations including full blood count, blood urea,
serum creatinine and coagulation profile should be performed. Urinalysis and urine culture
should be performed to rule out infection. Urine cytology can be performed if the patient is
at risk of bladder cancer however this may be difficult to interpret. Computed Tomography
(CT) with intravenous pyelography may be performed to rule out upper tract bleeding.
Rigid cystoscopy should initially be performed in all patients to further rule out bladder
malignancy and confirm the diagnosis of radiation cystitis. At this stage further clot
evacuation and fulguration with diathermy can be performed at this time if required. If
conservative measures fail, ablative therapies should be performed which may lead to
immediate control of the bladder haemorrhage. This process can be repeated if required. If
ablative resources are not available, then intravesical aluminium may be administered.
When minimally invasive measures are unsuccessful we recommend consideration of
bladder preserving urinary diversion with bilateral nephrostomies or an ileal conduit.
Embolisation can also be considered at this time. If bleeding persists despite urinary
diversion, intravesical formalin at a non-toxic concentration may be considered however
definitive cystectomy may at this stage be required. Finally, we suggest consolidation with
hyperbaric oxygen in patients undergoing bladder preservation treatment strategies once
bleeding has been controlled and the patient is stable.
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4.2 Haemorrhagic radiation cystitis with bothersome intermittent bleeding.
Bothersome intermittent bleeding can be defined as multiple episodes of frank haematuria
for which patients seek medical attention or microscopic haematuria resulting in a
haemoglobin drop that requires medical attention. As detailed above, these patients should
undergo thorough clinical investigation to rule out other cause for bladder haemorrhage.
Part of this diagnostic work up should initially include a rigid cystoscopy to further rule out
other cause for bleeding including bladder malignancy and enable diagnosis of radiation
cystitis. Bladder wash out and fulguration or ablation of bleeding or immanently bleeding
vessels can be performed at this time.
Hyperbaric oxygen for management of haemorrhagic radiation cystitis has the most robust
evidence for efficacy, however it is cumbersome for patients requiring long duration of
treatment and a certain level of fitness that many patients with radiation cystitis will not
achieve. Patients with intermittent self-limiting episodes of bleeding should be prescribed
hyperbaric oxygenation, where possible, and considered for medical systemic or intravesical
therapies. There are no direct comparative trials between oral and intravesical therapy for
the management of haemorrhagic radiation cystitis. As such, we advocate a step-by-step
management algorithm that can be tailored to the specific clinical situation of each patient
with consideration of the side effect profile and acceptability of the intervention. These
patients should also be offered regular follow-up appointments in the urology outpatients
department.
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Future perspectives and conclusions
The relationship between novel pelvic radiation techniques and haemorrhagic radiation cystitis will
             
completed. In the interim, many treatment options are available for the management of chronic
radiation cystitis, however level one evidence is lacking. Medical systemic therapies are appealing as
they are non-invasive but are most efficient for chronic haemorrhagic radiation cystitis. Hyperbaric
oxygen therapy is also non-invasive but requires commitment from patients and is not freely
available as a healthcare resource. Intravesical therapy is associated with an acceptable short-term
response rate, however limited evidence is available on durability. If laser ablative therapies are
required, selection of the green light spectrum is preferable due to its more favourable safety-profile
compared to YAG-laser. Most importantly, we advocate a stepwise management algorithm with
multimodal treatment in patients presenting with severe acute haemorrhagic radiation cystitis.
6.0 References
[1] Smit SG, Heyns CF. Management of radiation cystitis. Nature Reviews Urology. 2010 Apr:
7:206-14
[2] Zelefsky M. J CH, Hunt M, Yamanda Y, Shippy A and Amold H. Long-term outcome of high
dose intensity modulated radiation therapy for patients with clinically localised prostate cancer. . J
Urol. 2006: 176:1415-9
[3] Marks LBC, P R; Dugan, T C; Anscher, M S. The response of the urinary bladder, urethra, and
ureter to radiation and chemotherapy. [Review] International journal of radiation oncology, biology,
physics. 1995: 31:1257-80
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complications presenting to a urology department: a more common problem than previously
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Accepted Article
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Accepted Article
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Accepted Article
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Jun: 41:584-7
[44] B. Lamb CP, D. Christidis, DG. Murphy, N. Lawrentschuk and TE. Manning. Green Light Laser
for management of hemorrhagic cystitis a novel technique and initial results. BJU Int. 2018:
121:58-91
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late hemorrhagic radiation cystitis and proctitis. Gynecol Oncol. 2006 Jan: 100:179-84
[46] Sandhu SS, Goldstraw M, Woodhouse CR. The management of haemorrhagic cystitis with
sodium pentosan polysulphate. BJU Int. 2004 Oct: 94:845-7
Accepted Article
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... To reduce the loss of impermeability of the urothelium, glycosaminoglycan-based treatments have been used (mainly pentosan polysulphate). However, treatment times (over 6 months) and the high relapse rate (23% at 1 year) are significant limitations [85][86][87][88][89][90]. To reduce inflammation, drugs such as hydroxyzine, cimetidine and corticosteroids have been used. ...
... Hydroxyzine and cimetidine are used to reduce mast cell activation. These treatments have a low level of efficacy (<50%) and their effects stop when treatment is stopped [88,91,92]. As for corticoids, their action remains limited in time [93,94]. ...
... The effect of this is the development of a vasoconstriction that reduces bleeding. These two techniques are less effective (<50% with recurrence rates of 10 to 25% over 6 months) and painful for the patient [85,88,[95][96][97]. One last and more promising technique is hyperbaric oxygen therapy. ...
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Cystitis is a bladder disease with a high rate of prevalence in the world population. This report focuses on Interstitial Cystitis (IC), Hemorrhagic Cystitis (HC) and Chronic Radiation Cystitis. These pathologies have different etiologies, but they share common symptoms, for instance, pain, bleeding, and a contracted bladder. Overall, treatments are quite similar for abacterial cystitis, and include bladder epithelium protective or anti-inflammatory agents, alleviating pain and reducing bleeding. This review summarizes the mechanisms that the pathologies have in common, for instance, bladder dysfunction and inflammation. Conversely, some mechanisms have been described as present in only one pathology, such as neural regulation. Based on these specificities, we propose identifying a mechanism that could be common to all the above-mentioned pathologies.
... Dans le cadre des cystites, les lésions sont renforcées par l'activation des mastocytes qui contribuent à la perméabilité vasculaire et aux recrutements des cellules immunitaires. Plus particulièrement pour la CRC, des atteintes vasculaires des hématuries et des télangiectasies(Pascoe et al. 2019) ont été mises en évidence ; cependant les mécanismes sous-jacents ont été peu étudiés.Les mastocytes qui vont produire différentes protéines comme NGF et Cox2 entrainant la production de PGE2 favorisant la perméabilité vasculaire. Cette perméabilité facilite le recrutement de cellules immunitaires. ...
... hémorragique, elle doit être consolidée par une oxygénothérapie hyperbare(Gallego-Vilar et al. 2013;Pascoe et al. 2019;Rigaud et al. 2004;Smit and Heyns 2010;Vanneste et al. 2021).Les options de traitements chirurgicaux vont de la dérivation urinaire cutanée à la dérivation de l'anse iléale ou du côlon, avec ou sans cystectomie(Linder et al. 2014). Ces différentes méthodes ont, en plus de l'impact de la chirurgie, un impact mental (trouble de l'érection, sentiment de diminution physique…) et social important pour les patients. ...
Thesis
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La cystite radique chronique (CRC) est une pathologie consécutive à l'irradiation pelvienne caractérisée par une inflammation chronique pouvant évoluer vers une fibrose avec des symptômes de douleur et de saignements. Nos études antérieures sur la cystite radique ont montré que les cellules souches mésenchymateuses (CSM) limitent les effets chroniques de l'irradiation. L’objectif de cette thèse a été de mettre en place un modèle de CRC chez le rat puis d’évaluer l’efficacité des CSM et leurs mécanismes d’action. La CRC a été induite par une irradiation localisée en dose unique de la vessie entière avec deux faisceaux, guidée par la tomographie. Une gamme de doses de 20 à 80 Gy avec un suivi de 3 à 12 mois après l'irradiation a permis de caractériser l’effet dose et la cinétique de la CRC. Nous avons observé que l'intensité et la fréquence des hématuries sont proportionnelles à la dose d'irradiation avec un seuil à 40 Gy. Pour le traitement, la dose de 40 Gy a été retenue. Afin de potentialiser l’effet des CSM ont été injectées par voie intraveineuse avant la phase chronique. Trois injections de 5 millions de CSM ont été administrées toutes les deux semaines. Un suivi physiologique, histologique et moléculaire a été réalisé pendant 12 mois après l'irradiation. Les CSM ont permis de diminuer les lésions vasculaires ainsi que les atteintes de l’urothélium. Ces résultats sont une preuve de concept de l’efficacité des CSM. Cette première étude demandera à être approfondie au niveau des mécanismes, cependant il s’agit ici d’un réel espoir pour l’ensemble des patients souffrants de la cystite radique chronique résistant aux traitements conventionnels.
... Catheter placement with bladder irrigation may be necessary along with pelvic imaging or cystoscopy if patients are suspected to have a large clot burden. 5 When considering trauma as the etiology, it is important to note a foley catheter should not cause gross hematuria, even among patients on anticoagulation or antiplatelet therapies. 6 There are scenarios when traumatic balloon inflation in the prostate can cause gross hematuria; however, these patients still require evaluation by a urologist to discuss the risks, benefits, and alternatives to a gross hematuria workup. ...
... Post-RT pelvic complications are often moderate to severe, usually occurring following treatment for malignant pelvic tumors [5,6] . Recent reports list a 2% incidence rate and a risk of urethral narrowing for approximately 25 years following RT. ...
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Radiotherapy-induced urethral strictures (RIUS) decrease quality of life and present a great challenge for surgical reconstruction, especially due to proximal location, compromised vascular supply, and poor wound healing. It is unclear whether urethroplasty is an option in cases with stricture resulting from exposure to pelvic radiation. We review the pathophysiology, diagnostic workup, and disease-specific aspects of RIUS. Furthermore, we discuss several management alternatives such as excision and primary anastomosis, as well as techniques for open reconstruction with flaps. The most extensive techniques in the treatment of strictures include, for example, those using gracilis muscle flaps, as they can involve periurethral tissue to provide sufficient vascularity for excellent post-surgery urethral healing. In brief, RIUS represent a significant challenge. In carefully chosen patients, urethroplasty should be considered as a feasible and durable treatment. However, medical practitioners should always take into consideration that the results of urethroplasty in RIUS are not comparable to urethroplasties without a radiation background.
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Purpose Pelvic radiotherapy (RT) can cause debilitating bladder toxicities but few clinical interventions exist to prevent injury or alleviate symptoms. From a large GWAS in prostate cancer patients it was previously reported that SNPs tagging AGT, part of the renin-angiotensin system (RAS), correlated with patient-reported late hematuria identifying a potential targetable pathway to prevent RT-induced bladder injury. To investigate this association, we performed a pre-clinical study to determine if RAS modulation protected the bladder against RT injury. Methods C57BL/6 male mice were treated with an oral angiotensin converting enzyme inhibitor (ACEi: 0.3g/L captopril) 5 days before focal bladder X-irradiation with either single dose (SD) 30Gy or 3 fractions of 8Gy (8Gyx3 in 5 days). RT was delivered using XStrahl SARRP Muriplan CT-image-guidance with parallel-opposed lateral beams. ACEi was maintained for 20 weeks post RT. Bladder toxicity was assessed using assays to identify local injury that included urinalysis, functional micturition, bladder-released exosomes, and histopathology, and also an assessment of systemic changes in inflammatory-mediated circulating immune cells. Results SD and fractionated RT increased urinary frequency and reduced the volume of individual voids at >14 weeks, but not at 4 weeks, compared with non-irradiated animals. Urothelial layer width was positively correlated with mean volume of individual voids (p=0.0428) and negatively correlated with number of voids (p=0.028), relating urothelial thinning to changes in RT-mediated bladder dysfunction. These chronic RT-induced changes in micturition patterns were prevented by captopril treatment. Focal bladder irradiation significantly increased the mean particle count of urine extracellular vesicles and the monocyte and neutrophil chemokines CCL2 and MIP-2, and the proportions of circulating inflammatory-mediated neutrophils and monocytes, which was also prevented by captopril. Exploratory transcriptomic analysis of bladder tissue implicated inflammatory and erythropoietic pathways. Conclusions This study demonstrated that systemic modulation of the RAS protected against and alleviated RT-induced late bladder injury but larger confirmatory studies are needed.
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Silk-Elastinlike Protein-Based Polymers (SELPs) can form thermoresponsive hydrogels that allow for the generation of in-situ drug delivery matrices. They are produced by recombinant techniques, enabling exact control of monomer sequence and polymer length. In aqueous solutions SELP strands form physical crosslinks as a function of temperature increase without the addition of crosslinking agents. Gelation kinetics, modulus of elasticity, pore size, drug release, biorecognition, and biodegradation of SELP hydrogels can be controlled by placement of amino acid residues at strategic locations in the polymer backbone. SELP hydrogels have been investigated for delivery of a variety of bioactive agents including small molecular weight drugs and fluorescent probes, oligomers of glycosaminoglycans, polymeric macromolecules, proteins, plasmid DNA, and viral gene delivery systems. In this review we provide a background for use of SELPs in matrix-mediated delivery and summarize recent investigations of SELP hydrogels for controlled delivery of bioactive agents as well as their use as liquid embolics.
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Background: Radiation-induced hemorrhagic cystitis is a complication of pelvic radiotherapy, with an incidence of up to 5%. The resultant hematuria may be severe and refractory to conservative measures. Our objective was to describe the pattern of inpatient treatments among a cohort of patients with radiation-induced hemorrhagic cystitis requiring pharmacological management. Methods: We conducted a retrospective case series to identify all inpatient admissions at a single institution during which patients with radiation cystitis underwent pharmacological intervention for refractory hematuria between 2004 and 2019. Patient demographics, medical history, details of radiation therapy, and relevant admission data were collected. Details of treatment, including the use of pharmacotherapy and surgical treatment, were reviewed and summarized. Results: We identified 21 patients who were treated during 26 admissions. Most were male (91%) with a history of external beam radiation therapy (86%), primarily for prostate cancer (85%), and a median age of 73 (IQR: 67-85). Most patients received continuous bladder irrigation as the first intervention during their admission (65%), for a median duration of 40 hours (IQR: 25-59). Eleven separate pharmacologic agents were used, with variations in initial pharmacotherapy utilization over time. Most patients were treated with a combination of surgical and pharmacological interventions (85%). The median length of stay was 9 days (IQR: 5-17) and the 90-day readmission rate was 35%. Conclusions: Pharmacologic treatment for refractory radiation-induced hemorrhagic cystitis is inconsistent and lacks evidence to support treatment strategies. Further work is needed to determine the optimal management for this morbid complication.
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Doses of radiation leaked from a Varian Halcyon V1.0 multileaf collimator are measured experimentally. Profiles of beams with sizes of 1 × 2, 4 × 4, 10 × 10, and 16 × 16 cm² are measured using different detectors. It is found that doses of leaked radiation grow along with the size of the fields. Doses of radiation are additionally measured with the collimator completely closed. They are found to be in good agreement with the manufacturer’s data.
Article
Introduction & Objectives Radiation-induced haemorrhagic cystitis (RHC) is a frightening complication occurring after pelvic radiotherapy (PRT) which may significantly affect patients’ quality of life. Bladder instillation with glycosaminoglycan replacement therapy (GRT) including hyaluronic acid +/- chondroitin sulphate has been proposed as an emerging alternative to prevent relapses of haematuria. Strong points in favour of using GRT for RHC are the ease of administration, cost, almost absence of side effects and possibility of administration to outpatients. We investigated the effectiveness of GRT in a cohort, single-centre, of patients with past-medical history of PRT attending the outpatient clinic and/or the accident & emergency department (A&E) for RHC. Materials & Methods Patients with diagnosis of RHC, either with toxicity grade of 2 or 3, were deemed candidate for GRT as long as no active bleeding was occurring; in the case of non-self-limiting haematuria and/or anaemia for active bleeding, admission in the urology department was prompted for bleeding control prior to GRT instillation. An induction course of 6 weekly instillations was scheduled; if tolerated, patients were given a maintenance course with at least 6 monthly instillations. The primary end-point consisted in assessing the rate of haematuria remission (either partial or complete) defined as no need to readmission in the A&E and/or in the hospital. Secondary end-points included factors related to GRT failure. Univariate and multivariate analysis were undertaken to identify clinical independent variables associated to the events. Results Fifty-one patients with at least 1-year follow-up from the first GRT were included in the analysis. 88.2, 9.8 and 2% of patients had undergone PRT because affected by prostate, uterus and colorectal cancer, respectively. Median time-to-RHC was 31 months (IQR 21–90). Access to A&E and hospital admission were needed in 47 (92.1%) and 35 (68.6%) of the patients, respectively. Twenty-two (n = 22/35, 62.9%) patients required transurethral fulguration of the bladder, while the remainders could be managed with bladder wash-out. Median number of GRT instillations was 6 (IQR 3–7). Twenty-three (45.1%) patients needed to be readmitted to hospital a second time, receiving bladder wash-out (n = 7/23, 30.4%), transurethral fulguration of the bladder (n = 10/23, 43.5%) and/or cystectomy (n = 6/23, 26.1%). Ten (19.6%) patients received a second induction course of GRT. At the last follow-up, 36 (70.6%) patients did not required further hospital admission. Type of PRT and number of hospital admissions pre-GRT were the only variables statistically associated to the events at both univariate (P = 0.032 and P = 0.045) and multivariate analysis (P = 0.048 and P = 0.049). Conclusions GRT should be prompted as soon as possible after diagnosis of the haematuria and settling of active bleeding. Patients who had undergone adjuvant PRT after radical prostatectomy are those at higher risk of GRT failure.
Article
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Introduction: Hemorrhagic cystitis (HC) represents a challenging clinical entity. While various intravesical agents have been utilized in this setting, limited data exist regarding safety or efficacy. Herein, then, we evaluated the effectiveness and complications associated with intravesical alum instillation for HC in a contemporary cohort. Materials and Methods: We identified 40 patients treated with intravesical alum for HC between 1997-2014. All patients had failed previous continuous bladder irrigation with normal saline and clot evacuation. Treatment success was defined as requiring no additional therapy beyond normal saline irrigation after alum instillation. Results: Median patient age was 76.5 years (IQR 69, 83). Pelvic radiation was the most common etiology for HC (n=38, 95%). Alum use decreased patient's transfusion requirement, with 82% (32/39) receiving a transfusion within 30 days before alum instillation (median 4 units) versus 59% (23/39) within 30 days after completing alum (median 3 units) (p=0.05). In total, 24 patients (60%) required no additional therapy prior to hospital discharge. Moreover, at a median follow-up of 17 months (IQR 5, 38.5), 13 patients (32.5%) remained without additional treatment for HC. Adverse effects were reported in 15 patients (38%), with bladder spasms representing the most common event (14/40; 35%). No clinical evidence of clinically significant systemic absorption was detected. Conclusion: Intravesical alum therapy is well-tolerated, with resolution of HC in approximately 60% of patients, and a durable response in approximately one-third. Given its favorable safety/efficacy profile, intravesical alum may be considered as a first-line treatment option for patients with HC.
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Objective: Hemorrhagic cystitis is a challenging clinical entity with limited evidence available to guide treatment. The use of intravesical silver nitrate has been reported, though supporting literature is sparse. Here, we sought to assess outcomes of patients treated with intravesical silver nitrate for refractory hemorrhagic cystitis. Material and methods: We identified nine patients with refractory hemorrhagic cystitis treated at our institution with intravesical silver nitrate between 2000-2015. All patients had failed previous continuous bladder irrigation with normal saline and clot evacuation. Treatment success was defined as requiring no additional therapy beyond normal saline irrigation after silver nitrate instillation prior to hospital discharge. Results: Median patient age was 80 years (IQR 73, 82). Radiation was the most common etiology for hemorrhagic cystitis 89% (8/9). Two patients underwent high dose (0.1%-0.4%) silver nitrate under anesthesia, while the remaining seven were treated with doses from 0.01% to 0.1% via continuous bladder irrigation for a median of 3 days (range 2-4). All nine patients (100%) had persistent hematuria despite intravesical silver nitrate therapy, requiring additional interventions and red blood cell transfusion during the hospitalization. There were no identified complications related to intravesical silver nitrate instillation. Conclusion: Although well tolerated, we found that intravesical silver nitrate was ineffective for bleeding control, suggesting a limited role for this agent in the management of patients with hemorrhagic cystitis.
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Radiation cystitis is a recognised complication of pelvic radiotherapy. Incidence of radiation cystitis ranges from 23 to 80% and the incidence of severe haematuria ranges from 5 to 8%. High quality data on management strategies for radiation cystitis is sparse. Treatment modalities are subclassified into systemic therapies, intravesical therapies, and hyperbaric oxygen and interventional procedures. Short-term cure rates range from 76 to 95% for hyperbaric oxygen therapy and interventional procedures. Adverse effects of these treatment strategies are acceptable. Ultimately, most patients require multimodal treatment for curative purposes. Large randomised trials exploring emergent management strategies are required in order to strengthen evidence-based treatment strategies. Urologists encounter radiation cystitis commonly and should be familiar with diagnostic modalities and treatment strategies.
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The treatment of pelvic malignancies with radiotherapy can develop severe sequelae, especially radiation-induced hemorrhagic cystitis. It is a progressive disease that can lead to the need for blood transfusion, hospitalizations, and surgical interventions. This tends to affect the quality of life of these patients, and management can at times be difficult. We have evaluated the GreenLight Xcelerated Performance System (XPS) with TruCoag, although primarily used for management of benign prostatic hypertrophy (BPH), for the treatment of radiation-induced hemorrhagic cystitis. After International Review Board (IRB) approval, a retrospectivechart review was performed in addition to a literature search. A series of four male patients, mean age of 81 years, with radiation-induced hemorrhagic cystitis secondary to radiotherapy for pelvic malignancies (3 prostate cancer, 1 rectal cancer) were successfully treated with the GreenLight laser after unsuccessful treatment with current therapies described in the literature. All four patients treated with the GreenLight laser had resolution of their hematuria after one treatment and were discharge from the hospital with clear urine. The GreenLight XPS laser shows promising results for the treatment of patients with radiation-induced hemorrhagic cystitis, and deserves further evaluation and validation, especially since there is limited data available in the literature regarding the use of this technology for the treatment of this devastating condition.
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Intravesical instillation of glycosaminoglycans is a promising option for the treatment of chronic cystitis, as it supports the regeneration of the damaged urothelial layer. We investigated the efficacy of short-term intravesical chondroitin sulphate treatment (six courses of instillation) in patients with chronic radiotherapy- or chemotherapy-associated cystitis. This prospective, observational study included patients with chronic radiotherapy- or chemotherapy-associated cystitis, who received six once-weekly intravesical instillations of 0.2 % chondroitin sulphate 40 mL. Every week, patients recorded their symptoms and their benefits and tolerance of treatment, using a self-completed questionnaire. The study included 16 patients (mean age 68.5 years; 50 % male). During the study, a reduction in all evaluated parameters was observed. After one dose of chondroitin sulphate, symptom improvement was observed in 38 % of patients, and after the second dose, an additional 31 % of patients showed improvement. At week 6, 80 % of patients had either improved or were symptom free, and significant improvements in urinary urgency (p = 0.0082), pollakisuria (p = 0.0022), urge frequency (p = 0.0033) and lower abdominal pain (p = 0.0449) were observed. Haematuria, present in 9 of the 16 patients at baseline, was completely resolved in all cases after 6 weeks. The majority of patients (93 %) evaluated the tolerance of chondroitin sulphate as 'good' or 'very good'. No treatment-related adverse events were reported. Intravesical administration of chondroitin sulphate was effective for the treatment of radiotherapy- or chemotherapy-associated cystitis. Even short-term treatment appears to be effective in reducing symptoms and improving the quality of life of patients.
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Objective: Complications are an undesired side effect of any treatment and radiotherapy is no different. The aim of this study was to quantify the burden of these side effects in a tertiary referral urology department. Patients and methods: A prospective study of all urology admissions in a six-month period to a public urology department at a tertiary hospital was performed. Patients admitted with complications due to radiotherapy were included in the study. Data obtained included patient demographics, radiotherapy details, complication type and the management required. Results: A total of 1198 patients were admitted; 921 (77%) were elective and 277 (23%) were emergency admissions. 13 out of 921 (1.4%) of elective admissions and 20 out of 277 (7.2%) of emergency admissions were due to radiotherapy complications. Radiotherapy complications was the fourth most common reason for emergency admission, ahead of acute urinary retention. 21 patients accounted for these 33 admissions. 39 separate complications due to radiotherapy were diagnosed, with some patients having multiple complications. The median time to onset of complication was four years, IQR (1-9). The surgical intervention rate was 67%. The commonest procedures were washout with/without clot evacuation or diathermy in theatre (15.8%) and urethral dilatation/bladder neck incision (15.8%). Two urinary diversions and two cystoprostatectomy & urinary diversion was performed. Conclusion: Radiotherapy complications are consequential and account for a significant proportion of a tertiary urology department's emergency workload. These complications generally occur years after radiotherapy and frequently require surgical intervention. This article is protected by copyright. All rights reserved.
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Introduction: Hemorrhagic cystitis presents a difficult clinical challenge, yet data regarding treatment options is sparse. Here, we sought to evaluate outcomes of a contemporary cohort of patients treated with intravesical formalin for hemorrhagic cystitis. Methods: We identified a retrospective cohort of eight patients managed with formalin for hemorrhagic cystitis from 2000-2014. All patients failed prior measures, including bladder irrigation, clot evacuation, and other intravesical agents. Treatment success was defined as hematuria resolution during the given hospitalization without use of additional invasive therapies. We also evaluated treatment complications and additional treatments following hospital dismissal. Results: Etiology of cystitis was radiation for malignancy in all cases. The formalin concentration ranged from 1-4%, with escalation used in treatment failures. Five patients (62.5%) received a single dose of 1% formalin, two patients received two doses, and one patient received three doses. Notably, intraoperative cystography identified vesicoureteral reflux (VUR) in 50.0% of patients. Six patients (75.0%) achieved treatment success, with a median time to resolution of four days (range 1-17 days). Of those refractory to formalin, one was managed with indwelling nephrostomy tubes and one underwent cystectomy. Median followup was eight months. Of the responders, two eventually required cystectomy, one for recurrent hematuria and one for recalcitrant bladder neck contracture and bladder dysfunction. The remaining four patients (50%) required no additional therapy. Conclusions: Formalin remains an important tool for treating refractory hemorrhagic cystitis, with roughly 75.0% of patients requiring no additional therapy prior to hospital discharge. Notably, there is a risk of bladder dysfunction following formalin.
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Purpose: Selective transarterial embolization (TAE) of the internal iliac artery is a well-known alternative technique to control intractable bladder hemorrhage (IBH). We explored the short- and long-term effectiveness of, and clinical outcomes after, TAE in patients with IBH. Materials and methods: In this retrospective study, we reviewed the hospital records of 18 IBH patients non-responsive to conservative medications who underwent TAE between January 2003 and May 2014. The early- and long-term effectiveness of TAE was investigated in the context of hematuria control, complications, mortality, requirement for blood transfusions, and hematocrit level. Results: Sixteen of the 18 patients underwent endovascular treatment; the technical success rate was 88%. TAE allowed complete remission in 16 patients (100% clinical success). On follow-up, mean hematocrit (P=0.003) and hemoglobin (P=0.005) levels significantly improved. Thirteen of the 16 patients (81%) required no further emergency admission after TAE during a mean follow-up period of 18.1months (range, 3-105months). Conclusion: TAE is a feasible, effective, and safe technique in both the short- and long-term for the treatment of IBH.
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OBJECTIVES: To analyze the efficacy of hyperbaric oxygen for the treatment of radiation-induced hemorrhagic cystitis and to identify factors associated with successful treatment. METHODS: Clinical records from 176 patients with refractory radiation-induced hemorrhagic cystitis treated at the Portuguese Navy Center for Underwater and Hyperbaric Medicine, during a 15-year period, were retrospectively analyzed. Evolution of macroscopic hematuria was used to analyze treatment efficacy and correlated with other external variables. RESULTS: From a total of 176 treated patients, 23.9% evidenced other radiation-induced soft tissue lesions. After an average on 37 sessions, 89.8% of patients showed resolution of hematuria, with only 1.7% of adverse events. In our sample, hematuria resolution after treatment with hyperbaric oxygen was statistically associated to the need for transfusion therapy (P = 0.026) and the number of sessions of hyperbaric oxygen (P = 0.042). No relationship was found with the remaining variables. CONCLUSIONS: Refractory radiation-induced hemorrhagic cystitis can be successfully and safely treated with hyperbaric oxygen. Treatment effectiveness seems to be correlated with the need for transfusion therapy and the number of sessions performed.