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      Chemical- and radiation-induced haemorrhagic cystitis: current treatments and challenges


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          • To review the published data on predisposing risk factors for cancer treatment-induced haemorrhagic cystitis (HC) and the evidence for the different preventive and therapeutic measures that have been used in order to help clinicians optimally define and manage this potentially serious condition.

          • Despite recognition that HC can be a significant complication of cancer treatment, there is currently a lack of UK-led guidelines available on how it should optimally be defined and managed.

          • A systematic literature review was undertaken to evaluate the evidence for preventative measures and treatment options in the management of cancer treatment-induced HC.

          • There is a wide range of reported incidence due to several factors including variability in study design and quality, the type of causal agent, the grading of bleeding, and discrepancies in definition criteria.

          • The most frequently reported causal factors are radiotherapy to the pelvic area, where HC has been reported in up to 20% of patients, and treatment with cyclophosphamide and bacillus Calmette-Guérin, where the incidence has been reported as up to 30%.

          • Mesna (2-mercaptoethane sodium sulphonate), hyperhydration and bladder irrigation have been the most frequently used prophylactic measures to prevent treatment-related cystitis, but are not always effective.

          • Cranberry juice is widely cited as a preventative measure and sodium pentosanpolysulphate as a treatment, although the evidence for both is very limited.

          • The best evidence exists for intravesical hyaluronic acid as an effective preventative and active treatment, and for hyperbaric oxygen as an equally effective treatment option.

          • The lack of robust data and variability in treatment strategies used highlights the need for further research, as well as best practice guidance and consensus on the management of HC.

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          Most cited references118

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          Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer.

          Radiotherapy is an alternative to cystectomy in patients with muscle-invasive bladder cancer. In other disease sites, synchronous chemoradiotherapy has been associated with increased local control and improved survival, as compared with radiotherapy alone. In this multicenter, phase 3 trial, we randomly assigned 360 patients with muscle-invasive bladder cancer to undergo radiotherapy with or without synchronous chemotherapy. The regimen consisted of fluorouracil (500 mg per square meter of body-surface area per day) during fractions 1 to 5 and 16 to 20 of radiotherapy and mitomycin C (12 mg per square meter) on day 1. Patients were also randomly assigned to undergo either whole-bladder radiotherapy or modified-volume radiotherapy (in which the volume of bladder receiving full-dose radiotherapy was reduced) in a partial 2-by-2 factorial design (results not reported here). The primary end point was survival free of locoregional disease. Secondary end points included overall survival and toxic effects. At 2 years, rates of locoregional disease-free survival were 67% (95% confidence interval [CI], 59 to 74) in the chemoradiotherapy group and 54% (95% CI, 46 to 62) in the radiotherapy group. With a median follow-up of 69.9 months, the hazard ratio in the chemoradiotherapy group was 0.68 (95% CI, 0.48 to 0.96; P=0.03). Five-year rates of overall survival were 48% (95% CI, 40 to 55) in the chemoradiotherapy group and 35% (95% CI, 28 to 43) in the radiotherapy group (hazard ratio, 0.82; 95% CI, 0.63 to 1.09; P=0.16). Grade 3 or 4 adverse events were slightly more common in the chemoradiotherapy group than in the radiotherapy group during treatment (36.0% vs. 27.5%, P=0.07) but not during follow-up (8.3% vs. 15.7%, P=0.07). Synchronous chemotherapy with fluorouracil and mitomycin C combined with radiotherapy significantly improved locoregional control of bladder cancer, as compared with radiotherapy alone, with no significant increase in adverse events. (Funded by Cancer Research U.K.; BC2001 Current Controlled Trials number, ISRCTN68324339.).
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            Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update.

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              Pathophysiological aspects of cyclophosphamide and ifosfamide induced hemorrhagic cystitis; implication of reactive oxygen and nitrogen species as well as PARP activation.

              Cyclophosphamide (CP) and ifosfamide (IF) are widely used antineoplastic agents, but their side-effect of hemorrhagic cystitis (HC) is still encountered as an important problem. Acrolein is the main molecule responsible of this side-effect and mesna (2-mercaptoethane sulfonate) is the commonly used preventive agent. Mesna binds acrolein and prevent its direct contact with uroepithelium. Current knowledge provides information about the pathophysiological mechanism of HC: several transcription factors and cytokines, free radicals and non-radical reactive molecules, as well as poly(adenosine diphosphate-ribose) polymerase (PARP) activation are now known to take part in its pathogenesis. There is no doubt that HC is an inflammatory process, including when caused by CP. Thus, many cytokines such as tumor necrosis factor (TNF) and the interleukin (IL) family and transcription factors such as nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) also play a role in its pathogenesis. When these molecular factors are taken into account, pathogenesis of CP-induced bladder toxicity can be summarized in three steps: (1) acrolein rapidly enters into the uroepithelial cells; (2) it then activates intracellular reactive oxygen species and nitric oxide production (directly or through NF-kappaB and AP-1) leading to peroxynitrite production; (3) finally, the increased peroxynitrite level damages lipids (lipid peroxidation), proteins (protein oxidation) and DNA (strand breaks) leading to activation of PARP, a DNA repair enzyme. DNA damage causes PARP overactivation, resulting in the depletion of oxidized nicotinamide-adenine dinucleotide and adenosine triphosphate, and consequently in necrotic cell death. For more effective prevention against HC, all pathophysiological mechanisms must be taken into consideration.

                Author and article information

                BJU Int
                BJU Int
                Bju International
                Blackwell Publishing Ltd (Oxford, UK )
                November 2013
                11 October 2013
                : 112
                : 7
                : 885-897
                [1 ]University College Hospital London, UK
                [2 ]Hampshire Hospitals NHS Foundation Trust Bristol, UK
                [3 ]Bristol Oncology and Haematology Centre Bristol, UK
                [4 ]Frimley Park Hospital NHS Foundation Trust Surrey, UK
                [5 ]Beatson West of Scotland Cancer Care Glasgow, UK
                [6 ]Southampton General Hospital Southampton, UK
                [7 ]The Royal Marsden Sutton, UK
                [8 ]Northern Centre for Cancer Treatment Newcastle, UK
                [9 ]University Hospital Birmingham, UK
                [10 ]Whipps Cross Hospital, Barts Health NHS Trust London, UK
                [11 ]Wrightington, Wigan and Leigh NHS Foundation Trust Wigan, UK
                Author notes
                Heather Payne, University College London Hospitals, 250 Euston Road, London NW1 2PG, UK. e-mail: heather_payne@ 123456blueyonder.co.uk
                © 2013 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of British Association of Urological Surgeons.

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                : 13 June 2013

                radiation cystitis,chemical cystitis,haemorrhagic cystitis,sodium hyaluronate,hyperbaric oxygen


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