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A c t a s U r o l ó g i c a s E s p a ñ o l a s
Original – Prostate cancer
Practical treatment approach in radiation-
induced cystitis
R. Martínez-Rodríguez, J. Areal-Calama, O. Buisan-Rueda, C. González-Satue, J.
Sanchez-Macias, M. Arzoz-Fabregas, J. Gago-Ramos, S. Bayona-Arenas, L. Ibarz-
Servio and J.M. Saladié-Roig
Department of Urology, Germans Trias i Pujol Hospital, Badalona, Spain Practical treatment approach in radiation-induced cystitis
Received 30 November 2009; accepted 1 March 2010 Objective: Establish a pattern of behavior and treatment algorithm at the onset of hematuria in patients with a previous history of pelvic radiation, checking for this different treatment options reflected in the literature. Material and methods: Through performing a PubMed literature review of articles related to IC lies, searching items includes the different treatment options: intravesical hyaluronic acid, conjugated estrogens, pentosan polysulfate, oral Cáncer de próstata Guía de tratamiento aminocaproic acid, recombinant factor VIIa, hyperbaric chamber, embolization, aluminum intravesical, Helmstein ball and formalin. Limits the search to English or Spanish publications and excluding those related to animal experimentation. Results: Every option is exposed, referring to the physiopathology, dosage regimen and administration, side effects and treatment efficacy. Conclusions: Once patient hemodynamic stabilization is achieved, and after rule out bladder tumors injuries and /or haemathuria originating from the upper urinary tract, treatment should start rolling. To know different treatment options and patterns of administration will allow the urologist to obtain a higher rate of success in the 2009 AEU. Published by Elsevier España, S.L. All rights reserved. Keywords: Radiation-induced cystitis Haemathuria Radiotherapy Prostate cancer Treatment guide E-mail: dr.rmartinez@yahoo.es (R. Martínez-Rodríguez). 0210-4806/$ - see front matter & 2009 AEU. Published by Elsevier Españ a, S.L. All rights reserved. doi:10.1016/j. acuro.2010.03.005 Document downloaded from http://www.elsevier.es on 18/06/2010. Copy for personal use. Transmission of this document by any means or in any format is forbidden. ACTAS UROL ESP. 2010;34(7):603–609
The chronic phase in turn begins 6 months after radiotherapy. The Introduction
effect of radiation upon the bladder wall leads to ischemia, which in turn conditions changes at vascular and muscle level. Vascular endothelial When the bladder is exposed to radiation in the context of radiotherapy damage causes hyperplasia, occlusion and perivascular fibrosis. Muscle for pelvic tumors, a series of histopathological changes are induced that damage in turn causes smooth muscle fiber replacement by fibroblasts, in turn have clinical consequences. In addition to irritative micturition leading to fibrosis and a secondary reduction in bladder capacity and syndrome characterized by micturition urgency, pollakiuria and dysuria, compliance1. Both alterations increase bladder susceptibility to mucosal the appearance of hematuria of highly variable intensity represents one ulceration and bleeding, and even bladder perforation and the formation of the most complex complications which the urologist must deal with. The present article offers a succinct review of the available treatment options for radiation-induced cystitis, with the purpose of facilitating its practical management on the part of the urologist. Specifically, the aim of the study is to establish an intervention protocol Patient evaluation
and define a diagnostic algorithm capable of facilitating patient Patients with radiation-induced cystitis can develop clinical manifestations ranging from asymptomatic microhematuria to macrohematuria with clots and secondary urinary retention. Despite the Material and methods
establishment of a presumed diagnosis on the basis of the patient condition, it is always necessary to discard possible infections and/or A PubMed literature search was made of articles related to actinic or Urinary infection can exacerbate hematuria produced in the context of radiation-induced cystitis. The search keywords included those referred to the different treatment options: systemic, endovesical and/or physical Radiotherapy for ovarian or cervical cancer increases the risk of treatment procedures. These comprised the following: endovesical bladder cancer 2- to 4-fold, and males subjected to radiotherapy for hyaluronic acid, conjugated estrogens, pentosan polysulfate, oral prostate cancer have a 50% increased risk of developing bladder cancer3. aminocaproic acid, recombinant factor VIIa, hyperbaric chamber, The exclusion of bladder neoformations based on urethrocystoscopy and/or urinary cytology is mandatory in cases of macroscopic hematuria. formalinization. The terms actinic and radioinduced were also Endoscopy moreover offers an endoluminal view with characteristic No limits were applied in terms of the date of publication or the If hematuria persists despite continuous bladder irrigation and endovesical coagulation of the bleeding lesions, hemodynamic The search was limited to publications in Spanish and English, and stabilization of the patient is the objective to be pursued. With the animal experimentation studies were excluded. The level of scientific patient under stable conditions, the management best suited to each evidence was added corresponding to each of the options according to individual case should be considered, among the range of options the current classification, published in the clinical practice guides of the Ia: The evidence comes from metaanalyses of well designed, Treatment options
Ib: The evidence comes from at least one randomized, controlled trial. IIa: The evidence comes from at least one well designed, There is no definitive treatment for severe hemorrhagic cystitis. A number of management options must be considered, and there is a range IIb: The evidence comes from at least one well designed, quasi- of possible combinations4. The most widespread management options are indicated below, with a brief comment on their form of I I I : The evidence comes from well designed, non-experimental administration, efficacy and possible side effects. descriptive studies such as comparative studies, correlation studies or I V : The evidence comes from documents or opinions of expert committees, or clinical experiences of authorities of prestige. Histopathological considerations
The histopathological changes after radiation exposure occur in two phases: acute and chronic. The acute and subacute phases are observed between 3-6 months after treatment. Histopathologically, urothelial desquamation, atypias and eosinophilic infiltrates have been described1. Clinically, patients may experience micturition urgency, dysuria and/or pollakiuria. Macrohematuria is observed in 7.7% of the cases, and although it is more frequent between 6 months and 5 years after treatment3-5, this interval can be expanded from 6 weeks to 14 years2. Document downloaded from http://www.elsevier.es on 18/06/2010. Copy for personal use. Transmission of this document by any means or in any format is forbidden. ACTAS UROL ESP. 2010;34(7):603–609
vagina is to be covered, in order to avoid abrasion secondary to instillation fluid losses. Formalinization should start at low concentrations (1-2%), with increments if needed. The duration of instillation in turn should not exceed 15 min., with an intravesical pressure of less than 15 cmH2O. Intravesical treatments
Because of the potential complications of the technique, it should only be used when other more conservative options have failed. 1. Hyaluronic acid
Intravesical hyaluronic acid temporarily restores the deteriorated glycosaminoglycan layer of the luminal surface of the bladder wall, Systemic treatments
stimulating connective tissue replacement and subsequently facilitating epithelial cell nesting and recomposition. Its use is widely accepted in interstitial cystitis5,6 and has been proposed 4. Conjugated estrogens
as preventive cotreatment in recurrent urinary infections and in The mechanism of action whereby conjugated estrogens act in After bladder voiding, 40 mg of product are instilled in 50 ml of hemorrhagic cystitis has not been fully established. Such treatment is physiological saline solution – the patient being required to retain it for accepted to modulate cellular immune responses and cytokines, and to at least 30 minutes. The instillations are repeated once a week for the stimulate endothelial cell activity14. The use of conjugated estrogens in first month and then once monthly until symptoms control is achieved. hemorrhagic cystitis has been reported to be both effective15,16 and ineffective17. The relatively low cost of the treatment, its few side effects, ease of administration, and the fact that it does not condition ulterior 2. Irrigation with aluminum salts
treatment modalities, make it necessary to consider conjugated estrogens The administration of estrogens has been associated with Aluminum (as aluminum ammonium sulfate, aluminum hydroxide or as hypercoagulability18 and liver toxicity; as a result, liver enzyme and aluminum potassium sulfate) exerts a protein precipitate astringent effect serum bilirubin determinations are required before starting treatment. on the cell surface and in the interstitial spaces8. Such irrigation results The administration protocol described by Ordemann et al.19 consists of in diminished capillary permeability, contraction of the intercellular starting treatment with 6 mg/day fractionated into three doses, followed space, vasoconstriction, hardening of the capillary endothelium and a by gradual increments up to 12 mg/day and/or hematuria control. The reduction of the edema, inflammation and exudate9. resolution of hematuria has been reported to occur from as little as 8 After extracting the possible bladder clots, irrigation is started with 5 hours post-administration to as long as after 7 days. The treatment is liters of distilled water in which 50 g of aluminum are dissolved (1%), at prolonged for 5-16 weeks, with descending conjugated estrogen doses. This technique is safe, effective and generally well tolerated10. Side effects have been reported such as suprapubic pain and spasms during the instillations9, as well as complications derived from the toxicity of 5. Pentosan polysulfate sodium
aluminum, and allergic reactions to its salts. Aluminum toxicity may be seen in patients with renal failure and/or extensive damaged bladder Up to 5% of the pentosan polysulfate sodium administered via the oral surfaces that act as absorbing areas. The appearance of lethargy, route is excreted in urine20. Although the precise mechanism of action is confusion, metabolic acidosis or plasma aluminum elevations requires not known, this drug repairs the urothelial glycosaminoglycan layer and exerts an antiinflammatory effect21. Few studies have been published on the use of pentosan polysulfate sodium, and the patient series have been limited in size, though with long term follow-up that advocates the 3. Formalinization
efficacy of this treatment22,23. The few side effects, the absence of interactions with other treatments, and the relatively rapid results (1-8 weeks)24 make it necessary to consider this treatment as a first-line Intravesical formalinization or formalin instillation was described by Brown12 in 1969 as a method for controlling hematuria secondary to advanced bladder carcinoma. Despite reported success rates of over 80%, the potential side effects and complications of this procedure have limited its use. 6. Aminocaproic acid
The toxicity of formalinization is directly dependent upon the concentration of the formalin employed, and to a lesser extent on the The use of epsilon aminocaproic acid for the management of hematuria duration of exposure13. The data reported in this sense in the literature of bladder origin has been described by a number of authors, with different success rates. Its oral administration at a dose of 150 Toxicity is both local and systemic, secondary to absorption and mg/kg/day during 21 days was described by Stefani et al.25 as an metabolization to formic acid and formate. The effects include effective way of treating hematuria in 9 patients, with hardly any side effects. Its intravesical application was advocated by Singh et al.26 as a obstruction, ureteral strictures, acute tubular necrosis, vesicoileal and safe and effective option in 37 patients. vesicovaginal fistulas, bladder disruption and toxic myocardiopathy, It is necessary to discard possible blood dyscrasias before administering the drug, regardless of the route employed. The short After discarding the presence of vesicoureteral reflux with filling series published to date and the lack of continuity in its use make it cystography (or using Fogarty catheters to avoid reflux) and emptying necessary to view this treatment option with caution. the bladder of clots, the following recommendations can apply35: with the patient under general or epidural anesthesia, the genital area (skin and mucosal membranes) must be protected with vaseline, and/or the Document downloaded from http://www.elsevier.es on 18/06/2010. Copy for personal use. Transmission of this document by any means or in any format is forbidden. ACTAS UROL ESP. 2010;34(7):603–609
7. Recombinant factor VIIa
arteries, and finally small vessels that perfuse specific regions (i.e., supraselective embolization38). Such supraselective embolization has Recombinant coagulation factor VIIa favors fibrin clot formation at the made it possible to reduce the complications of the technique. site of vascular damage, forming a complex with the exposed tissue The most frequent problem is gluteal pain (gluteal claudication), factor and acting upon the activated platelets27. Its use has been resulting from embolization of the internal iliac artery and accidentally authorized in refractory bleeding in patients with inhibitors targeted to of the superior gluteal artery. Lower extremity necrosis has also been factors VIII and IX, in factor VII deficiency, and in Glanzmann described, secondary to migration of the occluding material, as well as thrombasthenia. This treatment has been reported to be effective in bladder wall necrosis, and rarely lower limb paraplegia due to patients with thrombocytopenia and platelet disorders, bleeding embolization of spinal arteries – with the consequent spinal cord associated with oral anticoagulation, severe traumatisms and liver diseases28, as well as in cases of severe bleeding in adult patients without The advantages of the technique are that it can be carried out under congenital coagulopathy or inhibitor development29. local anesthesia, and posterior treatment modalities are not conditioned Few randomized clinical trials have been published on the variety of uses of such therapy, and most publications correspond to clinical notes with small sample sizes. Scarpelini and Rizoli published a review on the use of recombinant factor VIIa (rFVIIa) in the different surgical areas – 10. Helmstein balloon distension
reporting a decrease in preoperative bleeding in the context of retropubic radical prostatectomy, after administering 20–40µg/kg of recombinant In 1966, Helmstein successfully used hydrostatic pressure therapy in factor VIIa30. However, in the mentioned study, the blood losses in the bladder tumor treatment, inducing tissue necrosis through compression control group were considerably higher than those considered acceptable in 27 of the 35 patients described40. He later proposed the same method The successful use of this treatment after radiotherapy has been Most of the series published in relation to this technique date back to reported in the gynecological setting31, when all other measures had before 1980. It is globally described as useful, simple, with few side effects, but offering only temporary action. Candidates for treatment with rFVIIa must meet the following The technique involves fitting a specifically designed balloon (a normal hematological criteria32: hematocrit > 24%; fibrinogen 50–100 mg/dl; balloon or condom can be used) to the sectioned extremity of a no. 18 platelet count > 50,000 x 109; and pH >7.2. In addition, administration Foley catheter. Under epidural anesthesia (in order to eliminate bladder must adhere to a series of clinical intervention measures33. The request for recombinant factor VIIa as treatment for radiation- induced cystitis falls within the category of “compassionate drug use”. The recommended dose is 90 µg/kg, and a second dose may be administered after 20 minutes if the desired effect is not achieved. A further number of doses has not been shown to be effective. Physical measures

8. Hyperbaric chamber

The administration of high-pressure oxygen stimulates angiogenesis in
irradiation-damaged tissues34. The sessions last 90 minutes on average,
administering 100% oxygen in chambers at a pressure of 2-2.5 Figure 1 and 2. Supraselective embolization with fibrin plugs.
atmospheres35. Treatment consists of one daily session, 5 days a week. tone), the balloon is inserted through the urethra into the bladder. The The number of sessions varies according to the different literature balloon is then inflated with saline to a pressure of 10-25 25 cmH2O sources, though a minimum of 15 and a maximum of 60 are above diastolic pressure18. This pressure must be maintained for 6 hours. recommended before considering other treatment options30-32. The Although in principle Helmstein recommended the posterior patients in the reported series received an average of 30 sessions. The administration of mannitol to deal with meatus edematization following start of therapy in the three months following the onset of hematuria compression, this practice has not been shown to offer advantages in implies higher success rates, with a reduction in the number of required other published series41. The hemostatic effect thus obtained persists for sessions18,19. Previous endovesical treatments do not modify the success rates of the hyperbaric chamber19. This treatment is well tolerated – the The most frequently described complication is bladder rupture, reported complications being auditory and visual barotraumas in isolated detectable by a sudden intravesical pressure change during the procedure. In practically all such situations conservative management is carried out with urethral catheterization. 9. Arterial embolization
11. Cystectomy
Therapeutic embolization for the control of hematuria of bladder origin was described as far back as 1974 by Hald et al., who occluded the Surgery is to be considered only when the above described options have Interruption of the blood supply yields success rates of about 90% Anatomical dissection may be complicated according to the radiation according to the literature37. The level of occlusion has been improved received and the time elapsed. The type of urinary derivation must be from initial embolization of the internal iliac artery to the anterior adapted to the individual patient characteristics, the degree of patient branch of the internal iliac artery, the superior and inferior vesical Document downloaded from http://www.elsevier.es on 18/06/2010. Copy for personal use. Transmission of this document by any means or in any format is forbidden. ACTAS UROL ESP. 2010;34(7):603–609
autonomy, the background disease, and the disease prognosis. 4. Denton AS, Clarke NW, Maher EJ. Intervenciones no quirúrgicas Historically, hypogastric artery ligation has been an option when para la cistitis tardía por radiación en pacientes que han recibido radioterapia radical de pelvis (Revision Cochrane traducida). En: La Biblioteca Cochrane Plus, 2008 Number 2. Oxford: Update Software Ltd. Available in: http://www. update-software.com. Proposed algorithm
(Translated from The Cochrane Library, 2008 Issue 2. Chichester,UK: John Wiley & Sons, Ltd.). In the event of hematuria in a patient subjected to pelvic radiotherapy, 5. Kallestrup EB, et al. Treatment of intersticial cistitis with Cystistat: the presence of bladder neoformations must be discarded, along with a hialuronic acid product. Scan Journal of Urology. 2005;39:143–7. hematuria of upper urinary tract origin. 6. Nordling J, Jorgensen S, Kallestrup E. Cystistat for the treatment of When hematuria is attributed to radiation-induced cystitis, progressive intersticial cistitis:a 3-year follow-up study. Urology. 2001;57(6 treatment should be provided after hemodynamic stabilization of the 7. Preventing radiation induced cistitis with hyaluronic acid. J Support Formalinization should be considered only in life-threatening situations where surgery is contraindicated. The following management algorithm 8. Ostroff EB, Chenault Jr OW. Alum irrigation for the control of massive bladder hemorrhage. J Urol. 1982;128:929–30. 9. Arrizabalaga M, Extramiana J, Parra JL, et al. Treatment of massive haematuria with aluminous salts. Br J Urol. 1987;60: 223– 10. Goswami AK, Mahajan RK, Nath R, et al. How safe is 1% alum irrigation in controlling intractable vesical hemorrhage? J Urol 11. Choong M, Walkden R, Kirby. The management of intractable Start outpatient hyaluronic instillations 12. Brown RB. A method of management of inoperable carcinoma of 13. Godec CJ, Gleich P. Intractable hematuria and formalin. J Urol. Urethrocystoscopy in operating room: clot extraction and 14. Deshpande R, Khalili H, Pergolizzi RG, et al. Estradiol electrocautery of suspect areas, with biopsy downregulates LPS-induced cytokine production and NFkB activation in murine macrophages. Am J Reprod Immunol. 15. Miller J, Burfield GD, Moretti KL. Oral conjugated estrogen therapy for treatment of hemorrhagic cystitis. J Urol. 1994;151: 16. Rodriguez Luna JM, Teruel JL, Vallejo J, et al. Control of massive hematuria in idiopathic hemorrhagic cystitis after administration of conjugated estrogen. J Urol. 1992;148: 1524–5. 17. Vance BJ. Hemorrhagic cystitis: failure of estrogen treatment. 18. Daly E, Vessey MP, Hawkins MM, et al. Risk of venous thromboembolism in users of hormone replacement therapy. 19. Ordemann R, Naumann R, Geissler G, et al. Encouraging results in the treatment of haemorrhagic cystitis with estrogen-report of 10 Conclusions
casers and review of the literature. Bone Marrow Transplantation. 2000;25:981–5. 20. Parsons CL, Mulholland SG, Anwar H. Antibacterial activity A brief account has been provided of the majority of available therapeutic options. There is no single or ideal treatment. Knowing the glycosaminoglycans. Infect Immun. 1979;24:552–7. different options and their administration protocols will allow the 21. Chiang G, PATRA P, Letorneau R, et al. Pentosan polysulfate urologist to secure a higher success rate in the difficult management of inhibts mast cell histamine secretion and intracellular calcium ion levels: an alternative explanation of its beneficial effect in intersticial cystitis. J Urol. 2000;164:2119–25. Conflicts of interest
22. Hampson SJ, Woodhouse CR. Sodium pentosan polysulphate in the Management of haemorrhagic cistitis:Experience with 14 patients. The authors declare no conflicts of interest. 23. Parson CL. Successful Management of radiation cistitis with sodium pentosan polysulfate. J Urol. 1986;136:813–4. 24. Sandhu S, Goldstraw M, Woodhouse C. The management of 1. Pavlidakey P, MacLennan G. Radiation Cystitis. Journal of haemorrhagic cystitis with sodium pentosan polysulphate. BJU. 2. Crew JP, Jephcott CR, Reynard JM. Radiation induced 25. Stefani M, English HA, Taylor AE. Safe and effective, prolonged haemorrhagic cystitis. Eur Urol. 2001;40:111. administration of epsilon aminocaproic acid in bleeding from the 3. Chan TY, Epstein JI. Radiation or chemotherapy cystitis with urinary tract. J Urol. 1990;143:559–61. „„pseudocarcinomatous‟‟ features. Am J Surg Pathol. 2004;28: 909. 26. Singh I, Laungani GB. Intravesical epsilon aminocaproic acid in Document downloaded from http://www.elsevier.es on 18/06/2010. Copy for personal use. Transmission of this document by any means or in any format is forbidden. ACTAS UROL ESP. 2010;34(7):603–609
management of intractable bladder hemorrhage. Urology. 1992;40:227–9. 27. Hedner U. Novoseven as a universal haemostatic agent. Blood Coagul Fibrinolysis. 2000;11(Suppl 1):107–11. 28. Goodnough LT. Utilization of recombinant factor VIIa(rFVIIa) in no-approved settings. Haematology (ASH Education program Book). 2004;1:466–70. 29. Lecumberri R, Paramo J, Hidalgo F, et al. Reducción de las necesidades transfusionales en hemorragias adquiridas graves mediante factor VII activo recombinante. Med Clin. 2005;125:252–3. 30. Scarpelini S, Rizoli S. ecombinant factor VIIa and the surgical patient. Current Opinion in Critical Care. 2006;12: 351–6. 31. Geisler JP, Linnemeier GC, Manahan KJ. Recombinant factor VIIa to treta late radiation-induced hemorrhagic cistitis: a case report. J Reprod Med. 2008;53:360–2. 32. Vicent JL, Rossaint R, Riou B. Recommendations on the use of recombinant activated factor VII as an adjunctive treatment for massive bleeding-a European perspectiva. Critical Care. 2006;10:R 120, doi:, doi:10.1186/cc5026. 33. Martinowitz U. Guidelines for the use of recombinant activated factor VII(frFVIIa) in controlled bleeding: a report by the Israelı´ Multidisciplinary rFVIIa Task Force. Journal of Thrombosis and Haemostasis. 2005;3:640–8. 34. Mathews R, Rajan N, Josefson L, et al. Hiperbaric Oxygen Therapy for irradiation induced hemorrhagic cystitis. Journal of Urology. 1999;161:435–7. 35. Chong KT, Kampson NB, Corman JM. Early hyperbaric oxygen therapy improves outcome for radiation-induced hemorrhagic cystitis. Urology. 2005;65:649–53. 36. Hald T, Mygind T. Control of life-threating vesical hemorrhage by unilateral hypogastric artery muscle embolization. J Urol. 1974;112:60–3. 37. McIvor J, Williams G, Southcott RD. Control of severe vesical haemorrhage by therapeutic embolisation. Clin Radiol. 1982; 33:561–7. 38. De Bernardinis E, Vicini P, Salvatori F, et al. Superselective embolization of bladder arteries in the treatment of intractable bladder haemorrhage. Int J Urol. 2005;12:503–5. 39. Palma Ceppi C, Reyes Osorio D, Palma Ceppi R, et al. Experience in superselective embolization of bladder arteries in the treatment of intractable haematuria. Actas Urol Esp. 2008;32:542–5. 40. Helmstein K. Treatment of bladder carcinoma by a hydrostatic pressure technique. Br J Urol. 1972;44:434–50. 41. Iveresen Hansen, Djurhuus J, Nestrom B. Hydrostatic pressure treatment for carcinoma of the bladder. Scand J Urol Nephrol. 1976;10:209–13. 42. England HR, Rigby C, Shepheard BGF. Evaluation of Helmstein‟s distension method for carcinoma of the bladder. Br J Urol. 1973;45:593–9.

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