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• W1986805800 abstract "Cyclophosphamide is a commonly used cytotoxic drug indicated in a broad range of benign and malignant conditions. It has clearlydefined acute and chronic urinary tract side-effects that can significantly complicate patient treatment and are potentially fatal. Haemorrhagic cystitis (HC) may occur during, or shortly after, the administration of cyclophosphamide or the related oxazophorine-alkylatingagent, ifosfamide.1 In the longer term, bladder fibrosis and upper-urinary-tract obstructioncan arise due to scarring at the vesico-ureteric junction or the more proximal ureter. Transitional cell carcinoma (TCC) of the bladderis a further long-term side-effect.2 These tumours appear to be generally high grade and aggressive in nature. Squamouscell carcinoma of the bladder may also be increased.3 This type of tumour is often associated with chronic inflammation ofthe urothelium (e.g. schistosomiasis, urolithiasis), although with cyclophosphamide this may just reflect the poor differentiationof many tumours. Although many reports suggest these complications are dose related, all have occurred with exposures of as littleas 4 g intravenously4, 5 and 50 g orally.6 Theupper urinary tracts are also at risk of haemorrhage and TCC as a result of cyclophosphamide exposure, but not to the same extentas the bladder.7, 8 Clinically, HC results in haematuria and irritative voiding symptoms. The initial symptoms may be similar to urinary infection, whichshould be excluded or aggressively treated. Viral infections (i.e. cytomegalo­virus and adenovirus), which can also occurin immunocompromised patients, as well as other causes of HC (graft vs host disease, radiation cystitis) should also be considered. Cyclophosphamide-relatedHC produces pathological changes of severe cystitis with ulceration and areas of necrosis.6, 9 Bladderfibrosis and telangiectasia may develop as a consequence of the inflammatory process. These can give rise to chronic irritative voiding symptomsdue to a small-capacity bladder, as well as recurrent haematuria. Both cyclophosphamide and ifosfamide are metabolized to a number of compounds that are excreted by the kidneys, including acrolein.Animal studies have shown that, in animal bladders, changes only occur after treatment with cyclophosphamide analogues that are metabolizedto acrolein.10 This compound is believed to be responsible for HC in humans, although chloroacetaldehydehas also been implicated.11 Although specific genetic changes have been documented in TCC of the bladder, there is no hereditary basis for this disease.12 Rather, it relates largely to environmental risk factors, which include smoking, occupationalexposure, compound analgesic abuse and parasitic infection. In Western society, smoking is currently the major risk factor for this disease.12 Cyclophosphamide is clearly a further significant environmental risk factor for TCC. Based onanimal data, TCC also appears related to acrolein.13 In patients receiving cyclophosphamide for non-­urological malignancy,the risk of subsequent TCC is approximately 2%, compared to 0.1% with non-oxazaphorine cytotoxics and 0.04% inthe general population.2 Cellular atypia on voided urine cytology is reported in up to 30% ofpatients after receiving high doses of cyclophosphamide, which may identify a group with particularly high risk of TCC.14 Therisk of TCC appears cumulative with time. In a study of patients receiving cyclophosphamide for non-Hodgkin’s lymphoma, 3.5% haddeveloped TCC at 8 years, rising to 10.7% at 12 years.5 Latency periods varying between 9 months and over 20 years have been reported.1 Limiting the exposure of acrolein to the urothelium can reduce the risks of HC and, probably, TCC. Aggressive hydration to inducea diuresis should be undertaken and intravenous fluid-loading is recommended in the acute setting. Cyclophosphamide may affect renaltubular function, therefore fluid retention can be a potential problem with this strategy.1 Alkalin­izationof the urine should be avoided, particularly if symptoms of cystitis occur, as this can potentiate the effects of acroleinon the urothelium.15 The co-­administration of sodium 2-mercapto-ethane sulfon­ate (mesna) at the timeof cyclophosphamide reduces haemorrhagic cystitis.9, 16 Mesna is a thiol that binds to the 4-hydroxymetabolites of oxazophorines (including acrolein)to produce inert thioethers. Its duration of action is much shorter than the generation of ­cyclophosphamide metabolites and,therefore, its admin­istration should continue after cyclophos­phamide has been ceased. However, the most effective means of administeringmesna (bolus vs continuous infusion) and optimal dose (generally 100−150% of cyclophosphamide) has not been determined.An oral preparation is also available, with the reported dosages up to twice that used intravenously.16 Several randomized studies have been undertaken to evaluate prophylactic strategies in patients receiving cyclophosphamide for bone-marrowtransplan­tation. In one study,17 100 patients were randomized to receive either: (i) mesna administeredin bolus fashion at 160% of the cyclophosphamide dose or (ii) intra­-venous hyperhydration (diuresis > 200 mL/h).No differences were observed between the two groups. A subsequent study of 200 patients evaluated ­intravenous hydration(250 mL/h) and either: (i) continuous bladder irrigation or (ii) a continuous mesna infusionat 100% of the cyclophosphamide dose (commencing 1 h prior to cyclophosphamide admin­istrationand continuing for 24 h after cyclophosphamide administration).18 In both groups, macroscopic haematuria occurred in 18% of cases. The group that receivedbladder irrigations reported greater discomfort and had more urinary infections than with mesna (27%vs 14%; P = 0.03).However, infectious problems were largely restricted to female patients (43.5%vs 5% in males; P = 0.001).In an earlier randomized prospective study, 61 bone-­transplant patients were randomized to receive mesna or hyperhydration.19 Macroscopic haematuria occur­red in 9/26 (35%) of the latter group compared to4/32 (12.5%) of those receiving mesna (P < 0.05). One confounding issue in this study was the concomitant use of urinaryalkalinization in the hyperhydration group, which may have exacerbated the urothelial effects of acrolein. Once established, treatment of HC can be difficult, particularly in the presence of leukopenia and thrombocytopenia.20 Cessationof cyclophosphamide and the placement of a large catheter and bladder irrigation to minimize further contact between acrolein and the urotheliumand to clear small clots may be all that is necessary. A general anaesthetic for cystoscopic clot evacuation may be required andshould be considered at an early, rather than late, stage. Despite these measures, ongoing bleeding may occur. Blood-product supportand repeat cystoscopies may be needed. Further measures to control bleeding include instillation of alum, formalin or hyperbaric oxygen,although all these treatments for HC are based on anecdotal, rather than substantive, evidence.20 Ultimately,a small percentage of patients will require cystectomy as the only means of controlling intractable bleeding. In a series of 100 patientswho developed HC from the Mayo Clinic, Rochester, USA,6 cystectomy was ultimately required in nine cases − two for subsequent TCC,two for intractable symptoms related to fibrosis and five to control haemorrhage. In this group, HC or its complications contributedto the death of the patient in 10% of cases and in 4% of cases was the sole cause identified. While HC may have occurred in patients who subsequently developed TCC, this is often not the case. One large study showed no increasedrisk of TCC following HC among patients receiving cyclophosphamide.5 Certainly, the absence of a history of HC does not preclude the possibility of subsequent TCC.As a consequence, urinary tract surveillance of all patients who have received cyclophosphamide and ifosfamide is required to identifytumours at an early, and hopefully treatable, stage. This should comprise regular urine microscopy and voided urine cytology at 6−12 monthintervals after treatment with these agents. Further investigation with intravenous urography and cystoscopy is needed if haematuriaor abnormal voided urine cytology is detected. Haematuria, particularly microscopic, will be relatively common in these patients as a result of telangiectasia.However, as a high-risk group for TCC, full investigation should be undertaken. The cumulative risk and long latency periods reportedmandates that this follow up should continue on an indefinite basis. This may be difficult − as the initial disease and itstreatment may be but a distant memory for both patient and physician. Clinicians who plan to use cyclophosphamide must be aware of the urinary tract complications associated with its use. These canbe life threatening and therefore the strength of evidence for the use of cyclophosphamide must be carefully considered in additionto the availability of alternative treatments. Prophylactic measures of aggressive hydration, with the addition of mesna or bladder irrigationsfor high-dose intravenous therapy, should be undertaken to minimize the risk of haemorrhagic cystitis. These measures may also reducethe risk of TCC. However, all patients should be closely monitored with consideration of upper urinary tract imaging and cystoscopyif the patient develops voiding symptoms, haematuria or abnormal voided-urine cytology. Patients must be advised of the early andlate risks associated with the use of cyclophosphamide and understand the need for indefinite follow up." @default.
• W1986805800 created "2016-06-24" @default.
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• W1986805800 date "2002-05-01" @default.
• W1986805800 modified "2023-10-16" @default.
• W1986805800 title "Cyclophosphamide and the urinary tract" @default.
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