Chemotherapy and radiation-related hemorrhagic cystitis in cancer patients

INTRODUCTION — Hemorrhagic cystitis (HC) is a sterile cystitis that is characterized by gross hematuria. It is most common in patients treated with ifosfamide and high-dose cyclophosphamide in the setting of bone and soft tissue sarcoma and hematopoietic cell transplantation, or as a late toxicity of pelvic radiation therapy (RT) when the bladder is within the radiation treatment field.

The etiology, manifestation, and treatment of HC secondary to systemic chemotherapy and RT will be reviewed here. Acute infectious cystitis and cystitis caused by intravesical instillation of Bacillus Calmette-Guerin (BCG), used in the management of urothelial bladder cancers, as well as BK-virus-associated hemorrhagic cystitis are discussed separately. HC in patients receiving prolonged oral or intermittent intravenous cyclophosphamide as an immunosuppressant for rheumatologic conditions such as autoimmune disease and vasculitis is also discussed elsewhere.

●(See "Acute simple cystitis in adult and adolescent females" and "Acute simple cystitis in adult and adolescent males".)

●(See "Infectious complications of intravesical BCG immunotherapy", section on 'Localized disease'.)

●(See "General toxicity of cyclophosphamide in rheumatic diseases", section on 'Hemorrhagic cystitis'.)

●(See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Prevention of drug-induced cystitis'.)

●(See "Overview and virology of JC polyomavirus, BK polyomavirus, and other polyomavirus infections", section on 'Hemorrhagic cystitis' and "Overview of infections following hematopoietic cell transplantation", section on 'Hemorrhagic cystitis'.)

ETIOLOGY AND PATHOPHYSIOLOGY

Chemotherapy — Various chemotherapeutic agents, including ifosfamide, cyclophosphamide, busulfan, doxorubicin, dacarbazine, fludarabine, and cabazitaxel, can cause either nonhemorrhagic or hemorrhagic cystitis (HC) (table 1). HC is most frequently described in patients receiving the oxazaphosphorine alkylating agents ifosfamide and cyclophosphamide [1,2].

Ifosfamide and cyclophosphamide are approved for use in a variety of malignancies, both in children and adults. Cyclophosphamide is also used as a component of conditioning regimens prior to hematopoietic cell transplantation and as an immunosuppressant in a variety of rheumatologic (eg, autoimmune disease, vasculitis), nephrologic (eg, minimal change nephrotic syndrome), dermatologic (eg, refractory pemphigus), and neurologic (eg, relapsing/remitting multiple sclerosis) conditions. (See "General principles of the use of cyclophosphamide in rheumatic diseases" and "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy" and "Minimal change disease: Treatment in adults" and "Management of refractory pemphigus vulgaris and pemphigus foliaceus" and "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults".)

For patients treated with cyclophosphamide and ifosfamide, HC is a complex inflammatory response that is induced by a toxic metabolite (acrolein), with subsequent activation of immunocompetent cells and release of many proinflammatory agents [3,4]. During hepatic metabolism of both cyclophosphamide and ifosfamide, acrolein is generated, filtered by the kidneys, and concentrated in the bladder [5,6]. Acrolein is a reactive, unsaturated aldehyde that causes cell death through upregulation of reactive oxygen species, and that activates inducible nitric oxide synthase, leading to the production of nitric oxide [7,8]. Both reactive oxygen species and nitric oxide produce peroxynitrite, which attacks cellular macromolecules (lipids and proteins) and causes DNA strand breaks that trigger overactivity of DNA repair enzymes [9,10]. Reactive oxygen species also allow nuclear factor kappa B (NF-kB) to enter the nucleus and turn on transcription of genes encoding proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin 11 (IL-11) [10]. The end result is cessation of protein production and damage to the integrity of the urothelium, with morphologic and histologic evidence of swelling, bleeding, and ulceration of the bladder mucosa.

Radiation therapy — Radiation cystitis is a late complication of pelvic radiation therapy (RT) that can occur months to years after RT is administered. (See 'Radiation therapy' below.)

After administration of pelvic RT that includes the bladder, the bladder mucosa is initially edematous and friable. Later, there is progressive endarteritis (which leads to obliteration of the submucosal vasculature, with subsequent ischemia and reperfusion injury) and fibrosis of the mucosa and submucosa, with the development of dilated, fragile telangiectatic blood vessels that tend to bleed [11].

INCIDENCE AND RISK FACTORS

Ifosfamide — The hemorrhagic cystitis (HC) seen with ifosfamide therapy was identified in early clinical trials and recognized as a dose-limiting toxic effect [12-14]. In early trials, large single ifosfamide doses produced gross hematuria in 100 percent of patients [15]. In a later study using ifosfamide 5 to 7 g/m² divided into four to six doses given over two to three days without specific uroprotection, the incidence of HC was 18 percent (versus 6 percent with cyclophosphamide 1 to 1.2 g/m²) [16]. In other studies, the reported overall incidence of HC among patients treated with fractionated dosing of ifosfamide without urothelial protection ranges from 18 to 40 percent [14,17]. In contrast, when ifosfamide is administered with the uroprotectant mesna, gross hematuria is uncommon (occurring in <5 percent of cases), and microscopic hematuria alone occurs in 5 to 18 percent of courses [18-20].

Prophylactic mesna is recommended for all patients receiving ifosfamide for cancer [21-23]. (See 'Mesna' below.)

Cyclophosphamide — HC was described shortly after the introduction of cyclophosphamide to clinical use in 1958; it affected 10 to 40 percent of patients, and it sometimes abated on withdrawal of the drug [24]. The incidence of HC is higher in individuals who receive higher individual (as in the setting of hematopoietic cell transplantation [HCT]) and larger cumulative cyclophosphamide doses (such as in prolonged oral therapy for rheumatologic conditions) [25]. However, cases are described after single intravenous cyclophosphamide doses of 500 to 600 mg/m² [26,27]. (See 'Patients undergoing hematopoietic cell transplantation' below and 'Nontransplant settings' below.)

Patients undergoing hematopoietic cell transplantation — Patients receiving a cyclophosphamide-containing conditioning regimen prior to HCT are at risk for HC. In several reports, the cumulative incidence is 8 to 17 percent [28-30]. HC is reported following both autologous and allogenic transplantation, and it is more common after a myeloablative regimen than a reduced-intensity conditioning regimen [29]. The median duration of HC in one study was 27 days [29].

Besides the use of cyclophosphamide in a conditioning regimen, other potential contributory factors for HC in these patients include viral infection with BK/JC polyomavirus, adenovirus, or cytomegalovirus [31-35], and higher doses of busulfan. As an example, a strong association between BK viruria and long-lasting HC after HCT has been described, which might also explain why some patients get HC after a cyclophosphamide-containing conditioning regimen for HCT, while others do not [29,36]. Early posttransplant HC (defined as occurring within 72 hours of the preparative regimen) is more frequently associated with high-dose cyclophosphamide, while later HC more often results from viral infections, such as BK polyomavirus and adenovirus type 11. (See 'Viral infections' below.)

Nontransplant settings — As noted above, the incidence of HC is higher in individuals who receive higher individual and larger cumulative cyclophosphamide doses [25]. Although cases are described after single intravenous cyclophosphamide doses of 500 to 600 mg/m², this is uncommon. Given the lower rates of HC with cyclophosphamide as compared with ifosfamide, and given the dose dependence of HC with cyclophosphamide, use of prophylactic mesna has been considered unnecessary with the "standard" doses of intravenous cyclophosphamide used for cancer treatment outside of the setting of HCT [21-23].

The risk of HC and use of mesna in patients receiving cyclophosphamide for rheumatologic disorders are discussed in detail elsewhere. (See "General toxicity of cyclophosphamide in rheumatic diseases", section on 'Hemorrhagic cystitis'.)

Genetic factors influencing risk with cyclophosphamide — Among patients receiving cyclophosphamide, genetic polymorphisms in genes involved with cyclophosphamide metabolism may influence the risk of HC [28,37]. As an example, heterozygosity for the ALDH3A1*2 allele, which mediates degradation of activated cyclophosphamide metabolites, has been associated with a nearly 12-fold increase in the risk of HC compared with the wild-type ALDH3A1 variant [37]. Others have found polymorphisms in the drug metabolizing enzymes glutathione S-transferase (GST) and cytochrome P450 2C9 (CYP2C9) to be associated with HC risk in pediatric patients undergoing HCT after a conditioning regimen that included busulfan and cyclophosphamide [28]. There are no published data on the genetic factors influencing risk of HC with ifosfamide.

Despite these data, current practice does not support the routine genotyping of any candidate gene to identify patients who might be at higher risk for HC in order to select more effective prophylactic therapy.

Radiation therapy — Acute radiation therapy (RT)-related cystitis occurring during therapy can be a common complication with conventionally dosed pelvic RT, although the incidence is highly variable. It is associated with irritative voiding symptoms (eg, dysuria, frequency, urgency, and nocturia) and bladder spasms, but not usually hematuria. (See "Treatment-related toxicity from the use of radiation therapy for gynecologic malignancies", section on 'Acute radiation cystitis'.)

HC is reported as a late complication in 6.5 to 9 percent of patients who have received full-dose, standard-fractionation pelvic RT for prostate or gynecologic cancer [38-40], but it is severe in less than 5 percent [41]. The likelihood of developing radiation-induced HC is related to the total RT dose, the dose per fraction, and the volume of the bladder irradiated. Higher total doses of radiation (ie, such as are administered using conformal or intensity-modulated RT) can be associated with focal injury and a higher risk of hematuria or ulceration [42,43]. As an example, in one series of 309 patients receiving intensity-modulated RT for high-risk prostate cancer (78 Gy in 39 fractions), at a median follow-up of one to four months, the most frequently observed grade 2 or higher genitourinary toxicity was hematuria (11 percent), with radiation cystitis observed in the majority [42]. Rates were highest in patients in whom a high volume of the bladder neck was exposed to >75 Gy. In addition to the dose and volume of the bladder irradiated [44], other risk factors include high rates of acute grade ≥2 genitourinary toxicity [45], use of androgen deprivation therapy, and a history of transurethral resection of the prostate [46].

SIGNS AND SYMPTOMS — The clinical presentation of hemorrhagic cystitis (HC) in cancer patients is highly variable, ranging from mild hematuria and bladder irritation (which can be managed with observation or with hydration and bladder irrigation) to gross hematuria with clots and life-threatening persistent hemorrhage. Gross hematuria is suspected because of the presence of pink, red, or brown urine. Notably, this color change does not necessarily reflect severe underlying disease, since as little as 1 mL of blood per liter of urine can induce a visible color change. In more severe cases, the urine is no longer translucent, rather it is thick (with a consistency that is similar to ketchup), and patients may pass blood clots of variable size/volume in their urine (picture 1). Disorders in hemostasis due to systemic manifestations of cancer or its treatment (eg, thrombocytopenia or disseminated intravascular coagulation), or anticoagulation can exacerbate bleeding in susceptible patients [47].

In addition to hematuria, patients may also experience lower urinary tract symptoms, such as urinary urgency, frequent urination of small volumes, the sensation of incomplete bladder emptying, and a painful burning sensation with urination. In men, bladder spasms may produce severe referred pain in the glans penis. While suprapubic discomfort may be encountered, flank or back pain should raise the possibility of upper urinary tract or bladder outlet obstruction. In cases of more severe bleeding, patients may present with urinary retention secondary to blood clots obstructing the bladder neck (also known as "clot retention").

For patients receiving cyclophosphamide or ifosfamide, bleeding usually develops 24 to 48 hours after a single dose and typically lasts four to five days. The interval between the onset of HC and prior radiation therapy (RT) varies from months to years after treatment [39,48]; HC can appear as late as 10 or 20 years after treatment [49,50].

Grading the severity of hemorrhagic cystitis — Several investigators and groups, including the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), have used various grading schemes based on the level of intervention required for therapy (table 2). Among patients who develop severe HC despite vigorous preventive measures, deaths are reported, although this is extremely rare [5,51].

Severity grading criteria for long-term bladder toxicity after RT are also available from the Radiation Therapy Oncology Group (RTOG) (table 3). However, the CTCAE criteria are used more often.

DIAGNOSTIC EVALUATION — The diagnosis of hemorrhagic cystitis (HC) is based on a typical clinical presentation including hematuria and lower urinary tract symptoms, after excluding other potential causes of the signs/symptoms (such as urinary tract infection, bladder tumor, local tumor extension, and urolithiasis) via a complete hematuria evaluation (ie, urine culture, cystoscopy, urine cytology, upper urinary tract imaging). (See "Etiology and evaluation of hematuria in adults", section on 'Initial evaluation'.)

A thorough history is needed to evaluate for likely contributing etiologies (including assessing for any prior urologic diagnoses or surgeries, chemotherapy and radiation therapy [RT] treatments, and anticoagulant, over-the-counter, and nontraditional medication use). An exhaustive history of past and present medications is important since some chemotherapeutic agents may produce cystitis years after exposure (eg, busulfan) [52,53].

Tempo and location of the evaluation — The initial evaluation of HC is guided by the patient's presentation. In mild cases, the evaluation should proceed as mentioned above (ie, urinalysis, urine culture) and can be carried out in an outpatient setting. For severe HC, hospital admission may be appropriate with the initial evaluation, focusing on rapid assessment of hemodynamic stability and ensuring adequate bladder drainage with hyperhydration. Once the patient is stabilized and adequate bladder drainage is secured, further evaluation with cystoscopy, urine cytology, and upper urinary tract imaging can proceed as above to identify contributing etiologies.

Components of the diagnostic evaluation — The components of the workup are urinalysis and urine culture to rule out bacterial infection in all patients; selected patients may require cystoscopy, urine cytology, and upper urinary tract imaging.

●All patients with signs or symptoms of gross hematuria and/or cystitis should undergo examination of the urine sediment and bacterial culture of a clean catch specimen to confirm hematuria and rule out underlying bacterial infection. (See "Sampling and evaluation of voided urine in the diagnosis of urinary tract infection in adults".)

In the absence of infection, if the hematuria is not severe (ie, grade 1 (table 2) and the temporal onset is immediately following a dose of ifosfamide or high-dose cyclophosphamide, it is reasonable to pursue hydration, and possibly higher doses of mesna, without additional workup. We would repeat the urinalysis four to six weeks after the inciting cause to document resolution, with referral/additional workup if it persists [54].

●For more severe cases or if the diagnosis is in question, cystoscopy is indicated to evaluate for bladder tumors and potentially localize the bleeding. HC is typically characterized on cystoscopy by diffuse oozing of the bladder mucosa with neovascularization and telangiectasias (picture 2); the presence of a discrete bleeding vessel is less common. In cases of severe bleeding, cystoscopy under anesthesia may also allow for fulguration of bleeding vessels and clot evacuation. (See "Etiology and evaluation of hematuria in adults", section on 'Cystoscopy'.)

●For severe cases or if the diagnosis is in question, evaluation of the upper and lower urinary tract with computed tomography (CT) urogram (if renal function allows) is needed to evaluate for renal or ureteral tumors, bladder or other pelvic masses, and urolithiasis. In severe HC, this allows for an assessment of the degree of clot burden in the bladder (image 1). If a CT urogram cannot be performed due to contraindications, magnetic resonance (MR) urogram, or renal ultrasound and retrograde pyelograms can be performed [54]. (See "Etiology and evaluation of hematuria in adults", section on 'CT urography'.)

●Viral cultures, cytology, and special molecular techniques may be required to demonstrate unusual pathogens in severely immunocompromised patients (eg, after hematopoietic cell transplantation [HCT]). If lesions are present on external genitalia, a smear and culture can be performed for direct fluorescent antibody detection and growth of herpes simplex virus. (See 'Viral infections' below.)

●A complete blood count, serum creatinine, and coagulation parameters (eg, prothrombin and activated partial thromboplastin times) should be assessed at presentation in cases of severe HC.

Differential diagnosis

Gross hematuria — The intermittent excretion of red to brown urine can be seen in a variety of clinical conditions other than bleeding into the urinary tract. (See "Etiology and evaluation of hematuria in adults".)

Infectious cystitis — Infectious agents responsible for cystitis in cancer patients include both bacteria, which commonly cause infections in immunocompetent patients, and more unusual pathogens. (See "Acute simple cystitis in adult and adolescent females" and "Acute simple cystitis in adult and adolescent males".)

Typical urinary pathogens include Escherichia coli, Proteus spp, Klebsiella spp, and Staphylococcus saprophyticus. Coagulase-negative staphylococci can occasionally produce cystitis in patients with indwelling bladder catheters or urinary tract pathology, but they are also frequent contaminants in a poorly collected specimen.

Intracellular pathogens such as Mycoplasma and Ureaplasma are rare causes of cystitis in the cancer patient. Herpes simplex virus can cause urethritis, but rarely cystitis. Candida albicans and Candida glabrata have been reported to cause cystitis that is often hemorrhagic in severely immunocompromised hosts. In the United States, parasitic pathogens are distinctly uncommon. However, Schistosoma haematobium infection should be considered in patients from endemic regions, such as Egypt.

In patients with bacterial cystitis, examination of the urine often demonstrates white blood cells and a few red blood cells. However, the absence of white blood cells in a patient who is neutropenic following chemotherapy does not exclude a urinary tract infection. In an immunocompetent host, bacterial colony counts of greater than 100,000 in the urine are considered diagnostic of a urinary tract infection. It is not yet resolved whether this threshold should be lowered in neutropenic patients. (See "Sampling and evaluation of voided urine in the diagnosis of urinary tract infection in adults" and "Diagnostic approach to the adult cancer patient with neutropenic fever", section on 'Routine laboratory tests'.)

Viral infections — HC is commonly seen following HCT. Among patients undergoing a cyclophosphamide-containing conditioning regimen prior to HCT, early posttransplant HC (defined as occurring within 72 hours of the preparative regimen) is frequently associated with the use of high-dose cyclophosphamide, while later HC more often results from viral infections, such as BK polyomavirus (BKPyV) and adenovirus type 11 (AdV-11). (See 'Patients undergoing hematopoietic cell transplantation' above.)

It is hypothesized that virally mediated HC represents the reactivation of a latent form of the virus in the posttransplant period. In one study, recipient seropositivity for AdV-11 was highly predictive for the development of AdV-11-induced HC following allogeneic HCT [33]. (See "Overview and virology of JC polyomavirus, BK polyomavirus, and other polyomavirus infections" and "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection".)

Viral HC can be dramatic in presentation, but it usually resolves spontaneously within less than two weeks with supportive care including hydration and pain control. Virus culture is rarely used to detect JC polyomavirus (JCPyK) and BKPyV infection outside of a research setting. Cytologic examination can be used to detect urinary shedding of polyomaviruses. The most characteristic abnormality of polyomavirus-infected cells is an enlarged nucleus with a single, large, basophilic intranuclear inclusion [55,56]. The most important aspect of the diagnostic evaluation is to ensure that there are not other treatable causes of the HC and to ascertain that the bleeding is coming from the bladder and not the kidneys. Bleeding from the kidneys would suggest that the viral infection also involves the kidneys and is not just a superficial infection of the bladder.

Tumor involvement — The differential diagnosis of HC in patients receiving cancer treatment also includes tumor involvement of the bladder. This could be due to direct tumor invasion from adjacent organs (including the original primary tumor treated with pelvic RT, in those cases), a local recurrence of primary bladder cancer, or a second primary arising in the bladder that may be related to the prior RT [57]. This diagnosis can usually be established with appropriate radiologic imaging, urine cytology, cystoscopy, and cystoscopic bladder biopsy, when indicated based on the initial evaluation.

Urolithiasis — Another consideration in the differential diagnosis of gross hematuria is urolithiasis, which typically does not produce clots. (See "Kidney stones in adults: Diagnosis and acute management of suspected nephrolithiasis".)

PREVENTION — The best treatment for hemorrhagic cystitis (HC) is prevention.

Cancer patients receiving ifosfamide and high-dose cyclophosphamide — For patients receiving daily ifosfamide at any dose or high-dose cyclophosphamide in the setting of hematopoietic cell transplantation (HCT), we recommend forced saline diuresis and mesna to prevent HC. We suggest against continuous bladder irrigation (CBI) in this setting. (See 'Mesna' below and 'Forced saline diuresis and continuous bladder irrigation' below.)

Although highly effective, the use of mesna and forced saline diuresis does not completely prevent HC in patients receiving ifosfamide or high-dose cyclophosphamide. Close monitoring during treatment and careful attention to the earliest symptoms of cystitis are important to prevent progression to more severe HC. Notably, irritative symptoms alone are not a contraindication to continued cyclophosphamide or ifosfamide therapy. (See 'Monitoring for hemorrhagic cystitis during treatment' below.)

Patients receiving high-dose cyclophosphamide or ifosfamide should be instructed to drink at least 2 L of fluid a day and to void at first sensation. Oral fluids should be ingested prior to sleep, and patients should awaken once during the night to empty the bladder. Men should be encouraged to stand to void rather than using a bedside urinal in a recumbent position; in our experience, the posterior wall of the bladder is often involved with HC, possibly because use of a bedside urinal at night may be associated with incomplete emptying of the bladder.

Mesna — In keeping with guidelines from the American Society of Clinical Oncology (ASCO), we recommend the use of mesna to prevent HC in all patients receiving ifosfamide and in those receiving high-dose cyclophosphamide in the setting of HCT [21-23]. (See 'ASCO guidelines' below.)

Mesna is a thiol compound that inactivates acrolein in the urine to reduce the risk of bladder toxicity from oxazaphosphorines such as cyclophosphamide and ifosfamide. Mesna has been shown to be an effective uroprotective agent in patients receiving these agents, and benefit has been confirmed in randomized trials conducted in cancer patients receiving both ifosfamide and high-dose cyclophosphamide [58-62].

Within minutes of intravenous administration, mesna is oxidized to a stable inactive disulfide in the serum, but it is reactivated in the kidney. In the urine, it binds to acrolein, creating an inert thioether that is excreted [63]. The serum half-life of mesna is 90 minutes, while cyclophosphamide and ifosfamide have half-lives of six and seven hours, respectively. As a result, multiple doses are necessary. Mesna must be present in the bladder at the time of chemotherapy administration in order to be effective.

Mesna can be administered intravenously (either continuous or bolus), subcutaneously (continuous) [64], or orally.

●Intravenous bolus mesna typically uses a dose equal to 60 percent of the total daily dose of ifosfamide (at doses <2.5 g/m² per day) or high-dose cyclophosphamide, divided into three aliquots and administered prior to and four and eight hours following chemotherapy [65]. However, administration of mesna at 100 percent of the total dose of ifosfamide, divided into two aliquots and administered prior to and four hours following treatment, was as effective and more convenient than three bolus injections of the same dose administered four hours apart [66].

●With continuous infusion regimens of ifosfamide, mesna may be administered as a single bolus dose equal to 20 percent of the total ifosfamide dose, followed by continuous infusion of mesna equivalent to 40 percent of the ifosfamide dose, continuing for 12 to 24 hours after ifosfamide completion [21]. Continuous intravenous administration may enhance the nephroprotective effect of mesna with ifosfamide (thought secondary to the metabolite chloroacetaldehyde) while maintaining its uroprotective effect [67].

●Oral formulations of mesna show sustained urinary excretion and urinary bioavailability approaching that of intravenous mesna [68]. The rate and amount of mesna excretion appear to be less variable over time and more prolonged among patients after oral than after intravenous administration [69-71]. The protective effect of combined oral and intravenous mesna appears to be equivalent to that of intravenous mesna alone [69,72].

ASCO guidelines — Guidelines are available from an expert panel of ASCO regarding the use, dosing, and schedule of mesna in patients receiving ifosfamide or high-dose cyclophosphamide as administered in the setting of HCT; the original 1999 guidelines [22] were upheld and not changed in either the 2002 or the 2009 update [21,23].

Ifosfamide

●Intravenous mesna – The daily dose of intravenous mesna is calculated to equal 60 percent of the total daily dose of ifosfamide, administered as three bolus doses given 15 minutes before and four and eight hours after administration of each ifosfamide dose, when the ifosfamide dose is less than 2.5 g/m².

For regimens that employ continuous infusion ifosfamide, mesna can be administered as an initial bolus dose equal to 20 percent of the ifosfamide dose, followed by continuous infusion of mesna equal to 40 percent of the ifosfamide dose, continuing for 12 to 24 hours after completion of the ifosfamide infusion.

The panel concluded that there was insufficient evidence on which to base a recommendation for use of mesna with high-dose ifosfamide (>2.5 g/m² daily) [21]. However, given the longer half-life of ifosfamide with higher dose therapy, more frequent and prolonged mesna dosing regimens may be needed. We use intravenous mesna at 100 percent of the ifosfamide dose for regimens using ifosfamide doses >2.5 g/m² per day for three to five days.

●Oral mesna – If the oral route is chosen, oral mesna is not recommended for the initial dose. Patients should receive an initial intravenous bolus injection of mesna equal to 20 percent of the ifosfamide dose at the time of ifosfamide administration, followed by oral mesna tablets at 40 percent of the daily ifosfamide dose, administered at two and six hours following each dose of ifosfamide. Thus, the total daily mesna dose is 100 percent of the ifosfamide dose when the oral route is used. This same dosing schedule is repeated on each day that ifosfamide is administered. If patients vomit within two hours of taking a dose of mesna, they should repeat the dose or receive an intravenous dose of mesna.

Cyclophosphamide — Given the low reported incidence of HC with standard doses of intravenous cyclophosphamide used for cancer outside of the transplant setting, ASCO does not recommend the routine use of mesna in these patients; mesna should be used with forced saline diuresis only in conjunction with high-dose cyclophosphamide administered in the HCT setting (typically 50 mg/kg or 2 g/m²) [22]. These 1999 recommendations were reiterated in both the 2002 and 2009 updates [21,23]. In this setting, we dose mesna at 80 to 100 percent of the cyclophosphamide dose and administer it over 24 hours.

Forced saline diuresis and continuous bladder irrigation — The ASCO expert panel on chemotherapy and radiation therapy (RT) protectants recommends that patients receiving high-dose cyclophosphamide in the setting of HCT receive mesna in conjunction with saline diuresis or saline diuresis alone [22]; this original recommendation from 1999 was upheld in two subsequent guideline updates [21,23]. We typically administer both saline diuresis and mesna in this setting. (See "Hematopoietic support after hematopoietic cell transplantation".)

In 1991, the use of forced saline diuresis (hyperhydration) was proposed as a more cost-effective method for uroprotection [73]. The effectiveness of forced saline diuresis (intravenous normal saline at 250 mL/hour and furosemide sufficient to maintain urinary output >150 mL/hour) was evaluated in a series of 100 consecutive patients undergoing allogeneic or autologous HCT with a high-dose cyclophosphamide conditioning regimen [74]. In this series, HC developed in 7 percent of patients, and it was clinically significant in only two. The cost was significantly less (USD $20 per course) than the cost of mesna (estimated USD $1500 per course).

Mesna has been compared with forced saline diuresis for uroprotection in patients receiving high-dose cyclophosphamide regimens in two separate randomized trials, and the results are mixed [60,73,75]:

●A randomized trial of 100 adult patients undergoing HCT with a cyclophosphamide-containing conditioning regimen failed to find a significant benefit for mesna plus 1.5 L/day of saline hydration versus 3 L/day of intravenous fluids plus furosemide [73].

●By contrast, in a second prospective randomized trial of 61 consecutive HCT patients, mesna plus 3 L of intravenous hydration daily during high-dose cyclophosphamide was more effective than 6 L of intravenous hydration plus diuresis [75].

A subsequent trial in 200 patients undergoing HCT with a cyclophosphamide-based conditioning regimen showed that the addition of mesna to forced saline diuresis was more effective than the addition of CBI [60]. Patients randomized to CBI received 200 mL/hour of normal saline, and those randomized to mesna received it by continuous intravenous infusion at 100 percent of the cyclophosphamide dose. The overall incidence of hematuria of any grade was significantly higher in the CBI group (76 percent) compared with the mesna group (53 percent; p = 0.007). However, the incidence of grade 3 and 4 hematuria was the same in both groups (18 percent). Moderate or severe discomfort or bladder spasms were more frequent in patients receiving CBI than in those receiving mesna (84 versus 2 percent, p <0.0001). Urinary tract infections were also more common in patients receiving CBI (27 versus 14 percent; p = 0.03).

Monitoring for hemorrhagic cystitis during treatment — Although highly effective, the use of mesna and forced saline diuresis does not completely prevent HC in patients receiving ifosfamide or high-dose cyclophosphamide [18-20,76,77]. There are insufficient data to make a recommendation regarding specific monitoring for HC in patients receiving mesna with ifosfamide or cyclophosphamide. In keeping with recommendations from ASCO, during treatment with ifosfamide and high-dose cyclophosphamide, we recommend obtaining a baseline pretreatment urinalysis and monitoring for the development of gross hematuria and for urine output during treatment [21]. (See 'ASCO guidelines' above.)

Issues related to rechallenge — For patients who develop HC during treatment with ifosfamide or cyclophosphamide, there are no data to inform the safety or advisability of rechallenge with the same drug. If the HC developed in a patient who either did not receive mesna or received suboptimal dosing of mesna, we would attempt retreatment using standard doses of mesna. However, if the HC developed despite the use of mesna, we would probably not rechallenge these individuals.

Non-cancer patients receiving cyclophosphamide — There are no established guidelines for the use of mesna for the prevention of bladder toxicity secondary to cyclophosphamide for treatment of rheumatic diseases, and practice patterns vary among clinicians. This subject is discussed in detail elsewhere. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Prevention of drug-induced cystitis'.)

Patients receiving pelvic radiation therapy — No specific recommendation can be made for prevention of late radiation cystitis in patients undergoing pelvic RT.

Amifostine — Amifostine is an aminothiol that is cytoprotective in several tissues, including hematopoietic progenitor cells, renal cells, myocardium, intestinal epithelium, neuronal cells, and bladder urothelium [78-81]. The proposed mechanism of action involves the production of an active thiol metabolite, which acts as an intracellular scavenger of free radicals.

Amifostine has shown potential value for the prevention of both gastrointestinal and acute bladder toxicity from radiation. As an example, in one randomized trial, 205 patients undergoing RT for advanced pelvic malignancies were randomly assigned to daily intravenous amifostine (340 mg/m² over three to five minutes daily, 15 to 30 minutes before RT) or no amifostine [82]. The rate of grade >2 acute bladder toxicity was significantly less in the amifostine group by week 4 (14 versus 5 percent), and this difference was even more pronounced at week 7 (33 versus 0 percent).

However, there are no data supporting the ability of amifostine to prevent late bladder toxicity, including HC. Despite the data from this trial, amifostine is not used clinically in modern RT treatment plans.

TREATMENT

General approach to intervention — If hematuria develops despite the use of preventive measures (in patients treated with ifosfamide or high-dose cyclophosphamide) or following pelvic radiation therapy (RT), numerous treatment options are available depending on the severity of hemorrhagic cystitis (HC). A management algorithm outlining our approach is provided (algorithm 1), and discussed in detail in the following sections.

An important point is that for patients who are actively bleeding, platelet counts should be maintained at >50,000/microL, and potentially correctable bleeding disorders (including use of medications such as anticoagulants or aspirin that might be associated with an increased risk of bleeding) should be addressed.

While there is no consensus on the optimal management of this condition, typically a stepwise approach to treatment is used, balancing the risks/benefits of each modality and the severity of the condition. Interventions for HC are similar regardless of the underlying etiology (chemotherapy versus RT). In general:

●Common Terminology Criteria for Adverse Events [CTCAE] grade 1 (table 2) – Mild HC with irritative lower urinary tract symptoms and without clots following ifosfamide or cyclophosphamide treatment is generally transient and does not necessitate transfusion or clot extraction/irrigation. Treatment generally requires only outpatient management with hydration, with or without anticholinergic bladder medications for management of bladder spasms. If the hematuria clears and a repeat urinalysis four to six weeks after the inciting event does not show persistent hematuria, we would not pursue further diagnostic workup. (See 'Diagnostic evaluation' above.)

●Persistent or more severe (CTCAE grade 2 to 3 (table 2)) HC – Persistent mild or moderate HC, with or without clots, necessitates more invasive initial management, such as continuous bladder irrigation (CBI) with normal saline, or cystoscopy under anesthesia, to extract clots and to identify and fulgurate bleeding sources (if identified). Successful treatment may also require instillation of astringents such as alum, aminocaproic acid, or silver nitrate.

HBO may be useful, especially for patients with radiation-induced HC, but it is limited to relatively stable patients with access to a hyperbaric chamber. Another potential option for radiation cystitis is antioxidant therapy with vitamins E and C. Although there are no published reports specific to radiation-induced HC, there are data on benefit in chronic radiation proctitis [83], a late toxicity for which the cause is the same. (See 'Radiation therapy' above and "Radiation proctitis: Clinical manifestations, diagnosis, and management", section on 'Other therapies with an unclear role'.)

●CTCAE grade 3 to 4 (table 2) – Severe HC requires transfusions, and in addition to cystoscopy under anesthesia (to extract clots and to identify and fulgurate bleeding sources) and intravesical agent instillation as above, it may require more intensive interventions, such as intravesical formalin instillation, iliac artery angioembolization, temporary or permanent urinary diversion, and/or cystectomy.

Initial management — The initial management of HC varies based on condition severity:

●For patients with mild HC (ie, grade 1 (table 2), including those with gross hematuria without clots, adequate bladder emptying (as assessed by postvoid residual), and lower urinary tract symptoms, conservative measures, including hydration and anticholinergic bladder medications (as needed for bladder spasms), may be used in an outpatient setting after urinalysis and urine culture to exclude infection [84].

●For patients presenting with the passage of blood clots (moderate or severe HC), initial management includes assessment of hemodynamic stability, hydration (or transfusion if needed), and ensuring adequate bladder drainage. Typically, in these scenarios, patients are admitted to the hospital for observation and interventions. (See 'Tempo and location of the evaluation' above.)

A large-bore (≥22 Fr) three-way Foley catheter is placed to allow for manual clot irrigation with saline. (See "Placement and management of urinary bladder catheters in adults", section on 'Specialized catheters'.)

If the urine clears following manual irrigation, subsequent conservative management with hydration alone may be sufficient. If the hematuria or clots persist despite manual catheter irrigation, CBI with normal saline may be initiated. Ensuring adequate fluid outflow from the three-way catheter while on CBI is important because if the outflow channel becomes blocked, the bladder will continue to distend with the fluid being instilled, which risks perforation. Notably, outflow obstruction can present as worsening abdominal pain or persistent bladder spasms.

●If the three-way catheter has repeated obstruction, the clots cannot be removed by hand irrigation, or the patient does not improve with saline CBI, the next step is cystoscopy under anesthesia. While there are no data on the time to resolution with saline CBI alone, without repeated obstruction, we typically utilize this strategy for two to four days if the above conditions are not met and the patient's hemodynamic parameters allow. Proceeding with cystoscopy under anesthesia allows for clot evacuation (picture 1), fulguration of bleeding vessels (if they are identified), and management of any bladder tumors (if present). Notably, given the typical diffuse mucosal bleeding in HC, identifying a discrete bleeding vessel is not common. In one report of 33 patients with HC associated with cyclophosphamide or RT, 14 (42 percent) had resolution of hematuria after a single cystoscopy under anesthesia including clot evacuation or fulguration [85]. Only 4 of 11 patients who initially did not respond had resolution after a total of two or more cystoscopies.

Traditionally, cystoscopic bladder fulguration has been accomplished with electrocautery; however, some small case series note successful use of lasers for coagulation [86,87]. In these studies, a GreenLight potassium titanyl phosphate (KTP) laser (530 nm wavelength) and a 980 nm diode laser were used to manage radiation-induced HC. In an additional study, a GreenLight Xcelerated Performance System (XPS) laser (1064 nm wavelength) was successfully used in four patients who had previously failed fulguration with electrocautery [88]. The GreenLight XPS laser was also used in a series of 12 patients requiring blood transfusion from radiation-induced HC. Of these, nine were successfully treated, two had improvement but required a repeat procedure, and one proceeded to more aggressive therapy [89]. Notably, attention must be paid to the depth of laser penetration and the risk of bladder and intestinal perforation; in at least one case, fatal intestinal perforation was reported following laser coagulation for radiation cystitis in a female patient [90].

Interventions for persistent or moderate hematuria — If despite the above measures, the patient has persistent gross hematuria, with or without clots, additional interventions, such as intravesical instillations and HBO, may be utilized. Notably, most of the data regarding intravesical agent instillation consist of retrospective case series. There is no consensus on the best way to manage those with persistent or severe gross hematuria despite these initial measures. In general, it is best to start with the least aggressive intervention that is least likely to exacerbate the HC and then progress to more aggressive measures only when necessary.

Alum — Given the efficacy and tolerable side effect profile of intravesical alum instillation, it is commonly the first intravesical therapy utilized when other more conservative measures have failed.

Alum (aluminum ammonium sulfate or aluminum potassium sulfate) is an astringent that induces hemostasis by precipitating protein over the bleeding surface. Since it has low cell permeability, its action is limited to the cell surface and interstitial spaces. Prior to intravesical alum instillation, it is important to ensure that all clot has been removed from the bladder, as clot removal after alum instillation can be challenging. Alum administration is typically performed with a 1 percent solution (50 g of alum dissolved in 5 L of sterile water) that is used to continuously irrigate the bladder via a three-way Foley catheter (250 to 300 cc/hour) [91].

The success of this approach can be illustrated by a retrospective report in which continuous intravesical irrigation with a 1 percent alum solution was administered to 60 patients with HC [91]. Bleeding was controlled in 60 percent, with the most common adverse event being bladder spasms. At a median follow-up of 17 months, 33 percent of the cohort needed no other treatments for HC.

Severe side effects after intravesical alum instillation are uncommon, most side effects resulting in local irritative voiding symptoms [92]. Toxicity from systemic absorption is less common; however, there are six reported cases in the literature of acute aluminum toxicity in patients with chronic kidney disease who received intravesical alum irrigation for HC [93-96]. Clinically, aluminum toxicity may present with mental status changes, malaise, speech changes, and seizures [94]. (See "Aluminum toxicity in chronic kidney disease".)

If aluminum toxicity is suspected, serum aluminum levels can be monitored; toxicity is reported at a mean level of 7.4 micromol/L [97]. Of note, in a study of 12 patients with normal renal function undergoing intravesical alum therapy, the mean serum aluminum level rose from 1.68 micromol/L at baseline to 3.36 micromol/L, without any episodes of clinical toxicity [98].

Aminocaproic acid — Aminocaproic acid is a synthetic lysine that decreases fibrinolysis by competitively inhibiting plasminogen and plasmin [99]. It can be given either as an intravesical instillation or orally, as the majority of the orally administered drug is secreted unchanged in the urine [100].

For patients with HC, aminocaproic acid is administered intravesically as 200 mg of aminocaproic acid per 1 L of normal saline, or orally in divided doses of 100 to 150 mg/kg per day. In several small case series, the reported success rates for use of aminocaproic acid by either route for HC are between 92 and 100 percent [101-103]. Potential adverse side effects include thrombotic complications, rhabdomyolysis, and myopathy. Importantly, if considered for oral administration, upper urinary tract bleeding must be ruled out (potentially via computed tomography [CT] urogram) before administration, as ureteral obstruction from upper tract clots has been reported.

Silver nitrate — Silver nitrate can be used for intravesical instillation; it is proposed that when instilled, the compound is converted into nitric acid, which causes chemical cauterization of the urothelium. Notably, the preparation must be made using sterile water rather than saline, as silver nitrate mixed with saline causes precipitation. Solution concentrations of 0.01 to 1 percent can be used; however, instillation under anesthesia is needed for concentrations ≥0.5 percent [104].

While largely discussed and referred to as an option for treatment, clinical data regarding the efficacy of silver nitrate in this setting are sparse. In our own experience, there has been limited success with this treatment modality [104]. As there is the potential for obstruction from precipitation after instillation, a cystogram should be performed to rule out ureteral reflux prior to intravesical instillation [105].

Hyperbaric oxygen — Where available, HBO may be useful, especially for patients with radiation-induced HC. However, HBO is limited to relatively stable patients who have access to a hyperbaric chamber.

The rationale for use of HBO is that it may promote healing by increasing tissue oxygenation and aid in angiogenesis [106,107]. HBO appears to be effective for both RT-induced and chemotherapy-induced HC, although the bulk of the efficacy data are in patients with radiation-induced HC. The clinical response rate (partial or complete resolution) in this setting in a pooled analysis of 602 patients with at least 12 months of follow-up was 84 percent (95% CI 76-91) [108-117]. The following data are available:

●The use of HBO was initially described in patients with radiation-induced HC [109]. Most of these patients had severe inflammation requiring blood transfusion, but they were hemodynamically stable enough to be confined to a hyperbaric chamber under the supervision of a registered nurse and without the direct presence of a clinician. All but one patient had failed prior therapy. The oxygen tension was raised slowly to 2 atm. Each session was two hours, and 60 sessions were planned, with a cystoscopic examination after 30 treatments. Twelve of 13 patients experienced durable cessation of HC. The single failure demonstrated full-thickness bladder necrosis at the time of bladder removal (cystectomy).

●Similar favorable results were reported in several more contemporary series, in which complete resolution or marked improvement in symptoms of HC was seen in 65 to 81 percent of patients, respectively, with a regimen of 100 percent oxygen at 2 to 2.5 atm for 90 to 120 minutes during 20 to 40 sessions [110-115,118]. In three of the studies, outcomes appeared better when patients were treated earlier in the disease course (ie, within six months of hematuria onset). Cystoscopies done at resolution of HC demonstrated resolution of the underlying pathology and return to normal bladder mucosa and function [110,111,118]. The most common reported side effect of HBO has been otalgia, which in one report, was seen in 33 percent of patients and resolved after placement of tympanostomy tubes [112].

●There are only two randomized trials of HBO for HC:

•HBO (100 percent oxygen at 2.5 atm for 60 minutes daily, seven days per week for 30 days) was compared with intravesical hyaluronic acid instillation (40 mg of hyaluronic acid instilled in the bladder by Foley catheter for at least 20 minutes weekly for one month and then monthly for the following two months) in one small randomized trial of 36 patients with radiation-induced HC [119]. There were no significant differences between the treatments at 12 months in terms of efficacy (complete response in 10 of 20 patients treated with HBO compared with 12 of 16 in the hyaluronic acid group; partial response in 7 of 20 versus 3 of 16, respectively). No adverse complications were seen in either group, other than an increase in urinary tract infections in the hyaluronic acid group (thought to be secondary to repeated catheterizations).

•On the other hand, benefit for HBO was shown in the RICH-ART (Radiation Induced Cystitis treated with Hyperbaric oxygen—A Randomised controlled Trial) trial, in which 87 individuals who had completed pelvic RT at least six months previously, who scored <80 in the urinary domain of the Expanded Prostate Index Composite (EPIC) score [120], and who had been referred to one of five participating Nordic HBO clinics due to symptoms of late radiation cystitis were randomly assigned to "standard care" only or standard care plus HBO (30 to 40 sessions of 100 percent oxygen breathed at a pressure of 240 to 250 kilopascals [kPa], equivalent to 2.36 to 2.46 atm) for 80 to 90 minutes daily [116]. Exclusion criteria included ongoing transfusion-dependent bleeding, permanent urinary catheter, bladder capacity <100 mL, fistula in the urinary bladder, prior HBO for late radiation injuries, and contraindication to HBO. Specific treatment in the control group was neither prescribed nor described, but it included the option of undergoing HBO after the fourth and final study visit, which took place approximately six to eight months postrandomization. Notably, eight patients withdrew consent after randomization (seven who were assigned to the control group), and the intent-to-treat analysis included 79 patients. The primary endpoint was patient-perceived urinary symptoms, assessed with EPIC from randomization to the final study visit. The difference between change in group mean EPIC score was 10.1 points (95% CI 2.2-18.1, p = 0.013, 17.8 points in the HBO group and 7.7 points with standard care). Previous studies of the EPIC urinary total score had shown that the minimal clinically important difference was 9 points or less [120,121]. When categorized according to this minimal clinically important difference, in the HBO group, 73 percent of patients improved by the fourth visit, 23 percent had no change, and 5 percent worsened. In the standard care group, 34 percent improved, 54 percent had no change, and 11 percent worsened. Long-term outcomes were not described.

Adverse events affected 17 of the 41 patients in the HBO group (41 percent). Six had temporary ear pain during pressurization of the hyperbaric chamber, and four had signs of barotrauma (with paracentesis of the tympanic membrane needed in one). Hyperoxia-induced transient myopia with visual changes was reported in five (12 percent). These events were felt to be clearly related to HBO. The relationship of other adverse effects to HBO (infection, transient muscle cramps or pain, hematuria, diarrhea, fatigue, nausea, headache) was uncertain.

Although initial control rates are high, there is a risk of hematuria recurrence, which in one series, was 73 percent at five years after treatment [122]. Limited data from case reports also support benefit for HBO in patients with cyclophosphamide-induced HC [123,124].

In the United States, HBO therapy is cleared for use by the US Food and Drug Administration (FDA) in patients with radiation-related injury (including cystitis) but not for chemotherapy-related HC.

Other interventions — Other less commonly used interventions for persistent or moderate HC are oral pentosan polysulfate sodium (PPS), conjugated estrogens, recombinant factor VIIa, and antioxidants. Most of the data suggesting benefit from any of these therapies come from small series and case reports, and optimal patient selection for any of these treatments is not established.

Pentosan polysulfate sodium — PPS is a low molecular weight heparin (LMWH)-like compound with anticoagulant and fibrinolytic effects that has been approved for symptomatic treatment of interstitial cystitis. Its proposed mechanism of action is reconstitution of the deficient protective glycosaminoglycan layer over the urothelium. Of note, pigmentary retinopathy has been reported with pentosan polysulfate use. Typically this occurred after three years of use or longer, although cases have been seen with shorter use. Patients treated with PPS should be undergo close ophthalmologic evaluation, including periodic retinal examinations. Further details are discussed separately. (See "Interstitial cystitis/bladder pain syndrome: Management", section on 'Pentosan polysulfate sodium as alternative'.)

In multiple series, oral PPS has been effective in controlling hematuria in both RT-induced and cyclophosphamide-induced HC [125-127].

●In a series of 14 patients with HC following RT, treatment with PPS resulted in complete control of hematuria in 10 patients, while three had partial control [125].

●In another report, oral PPS (100 mg three times a day) was used as the primary management for 60 patients with HC associated with pelvic RT or systemic chemotherapy [126]. In 31 of 51 evaluable patients, PPS was eventually discontinued or the dose was reduced without recurrence of hematuria.

Conjugated estrogens — The role of systemic estrogen therapy for treatment of HC is uncertain given the disparate data regarding benefit and the potential for adverse events, including hormone-dependent cancers and venous thromboembolism.

Several older, uncontrolled, small reports suggested that oral conjugated estrogens are a simple and effective treatment option for mild HC [128-131]; however, a more recent randomized study of conjugated estrogen (6.25 mg daily) for chemotherapy-induced HC following hematopoietic cell transplantation (HCT) in 56 patients did not demonstrate a benefit over the control group [132].

Recombinant factor VIIa — The role of intravenous recombinant factor VIIa is unclear. The available data are mixed, and any benefit appears to be transient.

A few case reports note benefit from intravenous infusion of activated recombinant factor VII (NovoSeven) in patients with refractory HC [133-137]. Notably, in three of these studies, the treatment response was transient, with all patients returning to their baseline level of HC within 24 hours [134,136,137]. Furthermore, in a randomized trial of 26 patients with mild or moderate HC, there was no aggregate benefit of recombinant factor VIIa in the management of bleeding complications following HCT. Specifically, having the bladder as the primary site of bleeding was significantly associated with a negative impact on the bleeding outcome [135].

Antioxidants — Another potential option for radiation cystitis is antioxidant therapy with vitamins E and C. Although there are no published reports specific to radiation-induced HC, there are data describing benefit in chronic radiation proctitis [83], a late radiation-related toxicity for which the cause is the same. (See 'Radiation therapy' above and "Radiation proctitis: Clinical manifestations, diagnosis, and management", section on 'Other therapies with an unclear role'.)

Severe and/or refractory hemorrhagic cystitis

Urinary diversion — Urinary diversion can be performed in a temporary or permanent nature with percutaneous nephrostomy tube placement. Typically, this is used in stable patients who have failed more conservative measures. In small case series, urinary diversion in this fashion has demonstrated success in the management of HC [138,139]. Given the limited morbidity of nephrostomy tube placement, it could be considered in conjunction with or following intravesical therapies.

Formalin — Given the inherent toxicity and the potential for long-term bladder dysfunction, formalin is typically reserved for severe cases of HC following failure of other intravesical therapies.

Formalin is a 37 percent aqueous solution of formaldehyde. Formalin acts by hydrolyzing proteins and coagulating the tissue on a superficial level, controlling hemorrhage in the mucosa and submucosa. Intravesical instillation of dilute formalin has been used for many years in the treatment of intractable HC [140-143]. Instillations typically start with a 1 percent formalin instillation under general or regional anesthesia, and if the treatment is not successful, the dose is later escalated. Instillations are typically performed following a cystogram (to ensure there is no bladder perforation or ureteral reflux), under low pressure (<15 cm H₂O), and with a short dwell time (10 to 15 minutes) [144-146]. Formalin is caustic, so in addition to the longer term risk of bladder dysfunction, there is a risk of ureteral stricture and injury to the genital skin and perineum if they are not adequately protected. With instillation, the catheter should be kept on slight tension to occlude the bladder neck and prevent urethral exposure. If ureteral reflux is present, the ureters can be obstructed with occlusive catheters prior to formalin instillation.

While acknowledging the increased risk with intravesical formalin instillation, there is evidence supporting efficacy:

●In an early study, 35 patients treated with RT for cervical cancer who developed HC and failed conservative therapy with hydration, bladder irrigation, and clot extraction underwent treatment with diluted formalin (1, 2, and 4 percent in 22, 10, and 4 patients, respectively) by passive irrigation for 20 to 30 minutes, followed by continuous saline irrigation for 24 to 48 hours [142]. Thirty-one (89 percent) had a complete response to a single instillation, but HC recurred in seven after a median of seven months. One percent formalin was as effective as 2 or 4 percent formalin. Minor complications occurred in 19 patients and included mild fever, frequency, dysuria, suprapubic pain, transient incontinence, unilateral hydronephrosis, ureterovesical reflux, and decreased bladder capacity not requiring diversion. Major complications occurred in 11 patients (31 percent) and included bilateral ureteral stenosis causing hydronephrosis, vesicovaginal fistula, decreased bladder capacity requiring diversion, and one death due to bleeding and formalin toxicity.

●A more contemporary series included eight patients with radiation-induced HC refractory to bladder irrigation, clot extraction, and other intravesical agents who were managed with intravesical formalin [144]. The concentration ranged from 1 to 4 percent, with escalation of dose used for treatment failures. Five patients received a single dose, two received two doses, and one received three doses. At a median follow-up of eight months, six had resolution of hematuria (75 percent), with a median time to resolution of four days. Two of these eventually required cystectomy, one because of recurrent hematuria and the other for bladder neck contracture and bladder dysfunction.

Vascular interventions and extirpative surgery — In patients with persistent severe HC despite the previous measures, or in those with life-threatening bleeding, iliac artery angioembolization and bladder removal (cystectomy) are "last resort" options.

Selective iliac artery embolization — Selective iliac artery embolization has been successfully utilized in cases of refractory HC or in acutely unstable patients, with resolution of bleeding in up to 92 percent of cases [147-149]. This is typically performed with placement of an occlusive material (eg, gel foam, coils, etc) in the anterior division of the internal iliac artery. This is occluded as its further branches provide blood supply to the bladder via the vesical arteries. Otherwise, selective embolization of the vesical arteries may be possible. In both cases, embolization is performed after the posterior division has branched off the internal iliac artery to avoid occluding the superior gluteal artery, which would result in gluteal pain [150]. Other rare severe complications, including bladder necrosis, and embolization of the occlusive material to distal arterial branches have been reported [151].

Cystectomy — Rarely, surgical removal of the bladder is needed to control hemorrhage. In the largest available series on cystectomy and surgical urinary diversion for HC, RT was the underlying etiology in 81 percent of cases [152].

Typically, this is accomplished with a simple cystectomy and ileal or transverse colon conduit formation (depending on what bowel segment is healthy in those with prior pelvic RT) [152-154]. Of all the treatments mentioned, cystectomy is a treatment of last resort, as it is associated with a high risk of perioperative complications and mortality [152]. In patients too ill for urinary diversion with an intestinal segment, the ureters can be ligated, and the patient can be managed with percutaneous nephrostomy tubes or cutaneous ureterostomy following cystectomy.

SUMMARY AND RECOMMENDATIONS

●Etiology – Hemorrhagic cystitis (HC) is a sterile cystitis with hematuria. It most often occurs in patients receiving ifosfamide or high-dose cyclophosphamide in preparation for hematopoietic cell transplantation (HCT), and is a late complication in 6 to 9 percent of patients receiving pelvic radiation therapy (RT). (See 'Incidence and risk factors' above.)

●Presentation and diagnosis – Clinical presentation ranges from mild hematuria and bladder irritation, to gross hematuria with clots and life-threatening persistent hemorrhage. Severity is graded based on the degree of hematuria and the intensity of therapy required (table 2). (See 'Signs and symptoms' above.)

A clinical diagnosis of HC is made in patients with hematuria and lower urinary tract symptoms, after excluding other potential causes; biopsy is not required. Workup includes urinalysis and urine culture; selected patients may require cystoscopy, urine cytology, and upper urinary tract imaging. (See 'Diagnostic evaluation' above.)

●Importance of prevention and monitoring – All patients receiving ifosfamide or high-dose cyclophosphamide require hyperhydration (intravenous normal saline at 250 mL/hour and furosemide sufficient to maintain urinary output >150 mL/hour). In addition, we recommend mesna in all patients receiving ifosfamide or high-dose cyclophosphamide in the setting of HCT (Grade 1B). (See 'Mesna' above.)

For most patients, we perform a pretreatment urinalysis and monitor urine output for the development of gross hematuria. (See 'Monitoring for hemorrhagic cystitis during treatment' above.)

●Treatment – Treatment depends on severity and does not differ by underlying etiology (chemotherapy versus RT). There is no consensus on the optimal management (see 'General approach to intervention' above). We use a stepwise approach that balances the risks/benefits of each modality and HC severity, which is outlined in the algorithm (algorithm 1) and summarized below:

•Mild – For patients with mild HC, we suggest conservative management (hydration and anticholinergic bladder medications for painful bladder spasms) rather than more aggressive interventions while performing initial diagnostic studies (Grade 2C) to exclude other etiologies. This is often performed in the outpatient setting. Mild HC includes grade 1 HC (table 2), and HC with gross hematuria without clots, adequate bladder emptying (as assessed by postvoid residual), and only lower urinary tract symptoms. (See 'Initial management' above.)

We repeat the urinalysis four to six weeks after the inciting cause to document resolution, with referral/additional workup if hematuria persists.

•Moderate or severe or blood clots – For patients passing blood clots or with moderate or severe HC (table 2), we first assess hemodynamic stability, maximize hydration (or transfusion if needed), and ensure adequate bladder drainage. Most patients are admitted to the hospital. Once the patient is stabilized and adequate bladder drainage is secured, we proceed with cystoscopy, urine cytology, and upper urinary tract imaging to identify contributing etiologies. (See 'Tempo and location of the evaluation' above.)

For patients with blood clots, we place a large-bore (≥22 Fr) three-way Foley catheter to allow for manual clot irrigation with saline. (See "Placement and management of urinary bladder catheters in adults", section on 'Specialized catheters'.)

If the urine clears following manual irrigation, we offer a trial of conservative management with hydration alone. If gross hematuria or clots persist despite manual catheter irrigation, we initiate continuous bladder irrigation (CBI) with normal saline.

If the three-way catheter has repeated obstruction, the clots cannot be removed by hand irrigation, or the patient does not improve with saline CBI, the next step is cystoscopy under anesthesia. For those without indications for cystoscopy, we typically continue saline CBI for two to four days as long as the patient's hemodynamic parameters allow.

•Persistent/refractory symptoms – If despite the above measures, the patient has persistent gross hematuria, with or without clots, therapy is individualized and prioritizes less invasive/toxic options when feasible. Options include (see 'Interventions for persistent or moderate hematuria' above):

-Intravesical instillations of alum, aminocaproic acid, or silver nitrate. Intravesicular instillation of formalin is more toxic and reserved for severe and/or refractory HC.

-Hyperbaric oxygen, especially for relatively stable patients with radiation-induced HC. (See 'Hyperbaric oxygen' above.)

-Antioxidant therapy with vitamins E and C. (See 'Antioxidants' above.)

-Temporary or permanent urinary diversion with percutaneous nephrostomy tube placement. (See 'Severe and/or refractory hemorrhagic cystitis' above.)

-Iliac artery angioembolization and cystectomy are "last resort" options reserved for those with life-threatening bleeding and/or persistent severe HC refractory to other measures. (See 'Vascular interventions and extirpative surgery' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Beverly Moy, MD, MPH, who contributed to an earlier version of this topic review.